![Steroidogenesis](https://upload.wikimedia.org/wikipedia/commons/1/13/Steroidogenesis.svg)
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s involved in steroid metabolism. They participate in three
metabolic pathways
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical re ...
:
bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary b ...
biosynthesis,
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...
and
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
metabolism. There are three
isozymes In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
of 5α-reductase encoded by the genes
SRD5A1,
SRD5A2, and
SRD5A3.
5α-Reductases
catalyze
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the following generalized
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
:
:a 3-oxo-5α-steroid + acceptor a 3-oxo-Δ
4-steroid + reduced acceptor
Where a 3-oxo-5α-steroid and acceptor are
substrates, and a corresponding 3-oxo-Δ4-steroid and the reduced acceptor are
products
Product may refer to:
Business
* Product (business), an item that serves as a solution to a specific consumer problem.
* Product (project management), a deliverable or set of deliverables that contribute to a business solution
Mathematics
* Produ ...
. An instance of this generalized reaction that 5α-reductase type 2 catalyzes is:
:
dihydrotestosterone
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
+
NADP+ testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
+
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
+ H
+
where dihydrotestosterone is the 3-oxo-5α-steroid, NADP
+ is the acceptor and testosterone is the 3-oxo-Δ4-steroid and NADPH the reduced acceptor.
Production and activity
The enzyme is produced in many tissues in both males and females, in the reproductive tract, testes and ovaries,
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
seminal vesicles
The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.
The vesicles are 5†...
,
prostate
The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
,
epididymis
The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...
and many organs,
including the
Nervous System
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
.
There are three
isoenzyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
s of 5α-reductase: steroid 5α-reductase 1, 2, and 3 (
SRD5A1,
SRD5A2 and
SRD5A3).
5α-Reductases act on 3-oxo (3-keto), Δ
4,5 C19/C21 steroids as its substrates; "3-keto" refers to the double bond of the third carbon to oxygen. Carbons 4 and 5 also have a double bond, represented by 'Δ
4,5'. The reaction involves a stereospecific and permanent break of the Δ
4,5 with the help of NADPH as a cofactor. A hydride anion (H−) is also placed on the α face at the fifth carbon, and a proton on the β face at carbon 4.
Distribution with age
5α-R1 is expressed in fetal scalp and nongenital skin of the back, anywhere from 5 to 50 times less than in the adult. 5α-R2 is expressed in fetal prostates similar to adults. 5α-R1 is expressed mainly in the
epithelium
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
and 5α-R2 the stroma of the fetal prostate. Scientists looked for 5α-R2 expression in fetal liver, adrenal, testis, ovary, brain, scalp, chest, and genital skin, using immunoblotting, and were only able to find it in genital skin.
After birth, the 5α-R1 is expressed in more locations, including the liver, skin, scalp and prostate. 5α-R2 is expressed in prostate, seminal vesicles, epididymis, liver, and to a lesser extent the scalp and skin.
Hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
expression of both 5α-R1 and 2 is immediate, but disappears in the skin and scalp at month 18. Then, at puberty, only 5α-R1 is reexpressed in the skin and scalp.
5α-R1 and 5α-R2 appear to be expressed in the prostate in male fetuses and throughout postnatal life. 5α-R1 and 5α-R2 are also expressed, although to different degrees in liver, genital and nongenital skin, prostate, epididymis, seminal vesicle, testis, ovary, uterus, kidney, exocrine pancreas, and the brain.
In adulthood, 5α-R1-3 is ubiquitously expressed.
Substrates
Specific substrates include
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
,
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
,
androstenedione,
epitestosterone
Epitestosterone, or isotestosterone, also known as 17α-testosterone or as androst-4-en-17α-ol-3-one, is an endogenous steroid and an epimer of the androgen sex hormone testosterone. It is a weak competitive antagonist of the androgen recepto ...
,
cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
,
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
, and
deoxycorticosterone Deoxycorticosterone (DOC), or desoxycorticosterone, may refer to:
* 11-Deoxycorticosterone (21-hydroxyprogesterone)
* 21-Deoxycorticosterone (11β-hydroxyprogesterone)
See also
* Deoxycortisol
* Deoxycortisone
* 11-Hydroxyprogesterone
{{Che ...
. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown.
Beyond reducing testosterone to dihydrotestosterone, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effects on cerebral function achieved by enhancing
GABAergic inhibition. These neuroactive steroid derivatives enhance GABA via allosteric modulation at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior. 5α-dihydrocortisol is present in the
aqueous humor
The aqueous humour is a transparent water-like fluid similar to plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the posteri ...
of the eye, is synthesized in the
lens
A lens is a transmissive optical device which focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements''), ...
, and might help make the aqueous humor itself.
Allopregnanolone and
THDOC
Tetrahydrodeoxycorticosterone (abbreviated as THDOC; 3α,21-dihydroxy-5α-pregnan-20-one), also referred to as ''allotetrahydrocorticosterone'', is an endogenous neurosteroid. It is synthesized from the adrenal hormone deoxycorticosterone by t ...
are
neurosteroids
Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coin ...
, with the latter having effects on the susceptibility of animals to seizures. In socially isolated mice, 5α-R1 is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. This down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.
5α-dihydroaldosterone is a potent
antinatriuretic agent, although different from
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:
::
![5α-Reductase Mechanism](https://upload.wikimedia.org/wikipedia/commons/c/c2/5%CE%B1-Reductase_Mechanism.png)
::: ''
+ + H+ -> + NADP+''
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.
Testosterone
5α-Reductase is most known for converting
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
, the male
sex hormone
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects ar ...
, into the more potent
dihydrotestosterone
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
:
Image:Testosteron.svg, Testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
Image:Androstanolone.svg, Dihydrotestosterone
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
The major difference is the Δ
4,5 double-bond on the A (leftmost) ring. The other differences between the diagrams are unrelated to structure.
List of conversions
The following reactions are known to be catalyzed by 5α-reductase:
*
Cholestenone →
5α-Cholestanone
*
Progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
→
5α-Dihydroprogesterone
5α-Dihydroprogesterone (5α-DHP, allopregnanedione, or 5α-pregnane-3,20-dione) is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopre ...
*
3α-Dihydroprogesterone →
Allopregnanolone
*
3β-Dihydroprogesterone
3β-Dihydroprogesterone (3β-DHP), also known as 3β-hydroxyprogesterone, or pregn-4-en-3β-ol-20-one (4-pregnenolone, δ4-pregnenolone), is an endogenous steroid. It is biosynthesized by 3β-hydroxysteroid dehydrogenase from progesterone. Un ...
→
Isopregnanolone
*
Deoxycorticosterone Deoxycorticosterone (DOC), or desoxycorticosterone, may refer to:
* 11-Deoxycorticosterone (21-hydroxyprogesterone)
* 21-Deoxycorticosterone (11β-hydroxyprogesterone)
See also
* Deoxycortisol
* Deoxycortisone
* 11-Hydroxyprogesterone
{{Che ...
→
5α-Dihydrodeoxycorticosterone
*
Corticosterone
Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rar ...
→
5α-Dihydrocorticosterone
5α-Dihydrocorticosterone (5α-DHC, 5α-DHB), also known as 11β,21-dihydroxy-5α-pregnane-3,20-dione, is a naturally occurring, endogenous glucocorticoid steroid hormone and neurosteroid. It is biosynthesized from corticosterone by the enzyme ...
*
Aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
→
5α-Dihydroaldosterone
5α-Dihydroaldosterone is a metabolite of aldosterone that is formed by 5α-reductase. It is a potent antinatriuretic agent similarly to but somewhat different from aldosterone. It is produced in the kidney
The kidneys are two reddish-b ...
*
Androstenedione →
5α-Androstanedione
Androstanedione, also known as 5α-androstanedione or as 5α-androstane-3,17-dione, is a natural product, naturally occurring androstane (5α-androstane) steroid and an endogenous metabolite of androgens like testosterone, dihydrotestosterone (DH ...
*
Testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
→
5α-Dihydrotestosterone
*
Nandrolone
Nandrolone, also known as 19-nortestosterone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate (brand name Durabolin). Nandrolon ...
→
5α-Dihydronandrolone
Structure
![5AR structure](https://upload.wikimedia.org/wikipedia/commons/6/64/5AR_structure.png)
5α-Reductase is a membrane bound enzyme that catalyzes the
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
dependent reduction of double bonds in steroid substrates to increase potency. The
crystal structure
In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystal, crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pat ...
of a homolog of
5α-reductase isoenzymes 1 and
2 has been found in ''
Proteobacteria
Pseudomonadota (synonym Proteobacteria) is a major phylum of Gram-negative bacteria. The renaming of phyla in 2021 remains controversial among microbiologists, many of whom continue to use the earlier names of long standing in the literature. The ...
'' (proteobacteria 5α-reductase). This exists as a
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
with a seven alpha-helix transmembrane structure housing a hydrophobic pocket that holds cofactor NADPH an
monooleinwhich occupies the steroid substrate binding pocket.
In insect cells monoolein is not found, but is subbed out for other androgens and inhibitors.
The integral seven transmembrane topology is likely conserved across species, with the N terminus in the
endoplasmic reticulum lumen
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
and the C terminus facing the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. High conformational dynamics of the cytosolic region likely regulate NADPH/NADP+ exchange.
Sequence conservation
In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor taxa ...
across known crystal structures has corroborated high conservation in enzyme structure.
Inhibition
The mechanism of 5α reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate.
5α-Reductase inhibitor drugs are used in
benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...
,
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
,
pattern hair loss
Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ...
(androgenetic alopecia), and
hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
for
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and ...
.
Inhibition of the enzyme can be classified into two categories: steroidal, which are irreversible, and nonsteroidal. There are more steroidal inhibitors, with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Researchers have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably,
polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
s (especially
linolenic acid
Linolenic acid is a type of naturally-occurring fatty acid. It can refer to either of two octadecatrienoic acids (i.e. with an 18-carbon chain and three double bonds, which are found in the '' cis'' configuration), or a mixture of the two. Lino ...
),
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
, and
green tea
Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since the ...
.
Riboflavin
Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in ...
was also identified as a 5α-reductase inhibitor .
Additionally, it has been claimed that
alfatradiol works through this mechanism of activity (5α-reductase), as well as the
Ganoderic acid
Ganoderic acids are a class of closely related triterpenoids ( derivatives from lanosterol) found in '' Ganoderma'' mushrooms. For thousands of years, the fruiting bodies of ''Ganoderma'' fungi have been used in traditional medicines in East Asia ...
s in
lingzhi mushroom
Lingzhi, ''Ganoderma lingzhi'', also known as reishi, is a polypore fungus ("bracket fungus") native to East Asia belonging to the genus ''Ganoderma''.
Its reddish brown varnished kidney-shaped cap with bands and peripherally inserted stem giv ...
, and the
Saw Palmetto
''Serenoa repens'', commonly known as saw palmetto, is the sole species currently classified in the genus ''Serenoa''. It is a small palm, growing to a maximum height around . It is endemic to the subtropical and tropical Southeastern United S ...
.
Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT, leading to increased testosterone and
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
. Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive
17β-hydroxysteroid dehydrogenase, oxidative
3α-hydroxysteroid dehydrogenase, and
3β-hydroxysteroid dehydrogenase enzymes.
Gynecomastia
Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...
,
erectile dysfunction, impaired cognitive function,
fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
, impaired liver function,
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
, and
depression, are only a few of the possible side-effects of 5α-reductase inhibition. Long term side effects, that continued even after discontinuation of the drug have been reported.
Finasteride
Finasteride inhibits two 5α-reductase isoenzymes (II and III), while
dutasteride
Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefi ...
inhibits all three.
Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC
50 of 69 nM, but is less effective with 5α-R1 till an IC
50 of 360 nM.
Finasteride decreases mean serum level of DHT by 71% after 6 months,
and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.
Dutasteride
Dutasteride
Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefi ...
inhibits 5α-reductase isoenzymes type 1 and 2 better than finasteride, leading to a more complete reduction in DHT at 24 weeks (94.7% versus 70.8%).
It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 mg/day over three months.
A second study with 3.5 mg/day for 4 months decreased intraprostatic DHT even further by 99%.
The suppression of DHT in vivo, and the report that dutasteride inhibits 5α-R3 in vitro
suggest that dutasteride may be a triple 5α reductase inhibitor.
Congenital deficiencies
5α-Reductase 1
5α-Reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength, which has been proposed to be due to lack of 5α-reductase type 1 expression in bone and muscle.
In 5 alpha reductase type 2 deficient males, the type 1 isoenzyme is thought to be responsible for their virilization at puberty.
5α-Reductase 2
Impaired 5α-reductase 2 activity can result from mutations in the underlying SRD5A2 gene. The condition, known as
5α-reductase 2 deficiency
5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in '' SRD5A2'', a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum of ...
, has a range of presentations as atypical appearances of the external genitalia in males. This is because 5α-reductase 2 catalyzes the transformation of testosterone to the potent androgen dihydrotestosterone, which is required for the proper masculinization of male genitalia.
5α-Reductase 3
When
small interfering RNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to MicroRNA, miRNA, and op ...
is used to knock down the expression of 5α-R3
isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
in
cell lines
An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
, there is decreased cell growth, viability, and a decrease in DHT/T ratios.
It has also shown the ability to reduce testosterone, androstenedione, and progesterone in androgen stimulated prostate cell lines by adenovirus vectors.
Congenital deficiency of 5α-R3 at the gene SRD53A has been linked to a rare, autosomal recessive condition in which patients are born with severe intellectual dysfunction and cerebellar and ocular defects. The presumed deficiency is reduction of the terminal bond of polyprenol to dolichol, an important step in N-glycosylation of proteins, which in turn is important for proper folding of
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
residues on nascent
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
in the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
.
Nervous system
Affective disorders
Isolation rearinghas been shown to lower protein expression of 5α-reductase isoenzymes 1 and 2 in
cortical and subcortical brain regions of rat models. However, the amount of 5α-reduced
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
remained unaffected. This means isolation rearing likely leads to changes in the expression and activity of 5α-reductase in the brain, leading to dysregulation of
dopamine neurotransmission, resulting in
early chronic stress Treatment with
finasteride, a 5α-reductase inhibitor, has been shown to mimic the effects of
SSRI’s causing
sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction as ...
. Research has shown that 5α-reductase is the rate-limiting enzyme in
neurosteroid synthesis, specifically in the conversion of
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
to
allopregnanolone,
low levels of allopregnanolone has been tied to
depression,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
and
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
.
Sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary ...
can enhance 5α-reductase expression and activity in the
prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...
, leading to
mania
Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...
-related symptoms in rats.
It is also contested whether the use of 5α-reductase inhibitors is associated with
suicidal ideation and depression in patient populations who use them for
benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...
.
These symptoms have been found during active use of inhibitors and in immediate followup.
However, it is unknown if these symptoms arise naturally from benign prostatic hyperplasia.
Hypothalamic–pituitary–adrenal axis dysfunction
An alternative mechanism of
cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
regulation is regulated via 5α-reductase which catalyzes an A-ring reduction of cortisol, metabolizing the compound. Type 1 and 2 of 5α-reductase are the principal enzymes involved in cortisol clearance through the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. Excess cortisol has been tied to
non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
(NAFLD), but
in-vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology and ...
studies have found that an over expression of 5α-reductase type 2 can suppress
lipogenesis
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...
. The key role of 5α-reductase in cortisol breakdown and fat buildup has elucidated some of the side effects of 5α-reductase inhibitors. In randomized studies on human volunteers it was found that 5α-reductase inhibition through the use of
dutasteride
Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefi ...
and
finasteride can lead to hepatic lipid accumulation in men. In critical illness, overstimulation of cortisol as part of a stress response can lead to decreased clearance of cortisol through the liver via 5α-reductase and kidneys via
11β-hydroxysteroid dehydrogenase type 2,
longterm elevation of cortisol can lead to
Cushing's syndrome
Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...
.
Nomenclature
This enzyme belongs to the family of
oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
s, to be specific, those acting on the CH-CH group of donor with other acceptors. The
systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature.
A semisystematic name or semitrivial ...
of this enzyme class is ''3-oxo-5α-steroid:acceptor Δ
4-oxidoreductase''. Other names in common use include:
* 5α-Reductase
* 3-Oxosteroid Δ
4-dehydrogenase
* 3-Oxo-5α-steroid Δ
4-dehydrogenase
* Steroid Δ
4-5α-reductase
* Δ
4-3-Keto steroid 5α-reductase
* Δ
4-3-Oxo steroid reductase
* Δ
4-3-Ketosteroid-5α-oxidoreductase
* Δ
4-3-Oxosteroid-5α-reductase
* 3-Keto-Δ
4-steroid-5α-reductase
* Testosterone 5α-reductase
* 4-Ene-3-ketosteroid-5α-oxidoreductase
* Δ
4-5α-Dehydrogenase
* 3-Oxo-5α-steroid:(acceptor) Δ
4-oxidoreductase
See also
*
Steroidogenic enzyme __NOTOC__
Steroidogenic enzymes are enzymes that are involved in steroidogenesis and steroid biosynthesis. They are responsible for the biosynthesis of the steroid hormones, including sex steroids (androgens, estrogens, and progestogens) and cortic ...
*
Acne vulgaris
*
Cholestenone 5α-reductase
*
Hirsutism
Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a "male" pattern of hair growth in a female that ...
*
Lower urinary tract symptoms
Lower urinary tract symptoms (LUTS) refer to a group of clinical symptoms involving the bladder, urinary sphincter, urethra and, in men, the prostate. The term is more commonly applied to men—over 40% of older men are afected—but lower urin ...
*
Polycystic ovarian syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
*
List of steroid metabolism modulators
References
Further reading
*
External links
*
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