Cytochrome P450 3A5 is a
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 ...
that in humans is encoded by the ''CYP3A5''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Tissue distribution
''CYP3A5'' encodes a member of the
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the prostate and the liver.
It is also expressed in epithelium of the small intestine and large intestine for uptake and in small amounts in the bile duct, nasal mucosa, kidney, adrenal cortex, epithelium of the gastric mucosa with intestinal metaplasia, gallbladder, intercalated ducts of the pancreas, chief cells of the parathyroid and the corpus luteum of the ovary (at protein level).
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Clinical significance
The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. The enzyme metabolizes drugs such as nifedipine and cyclosporine as well as the steroid hormones testosterone, progesterone and androstenedione. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. This cluster includes a pseudogene, ''CYP3A5P1'', which is very similar to ''CYP3A5''. This similarity has caused some difficulty in determining whether cloned sequences represent the gene or the pseudogene.
CYP3A4/3A5 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Immunoblot analysis of liver microsomes showed that CYP3A5 is expressed as a 52.5-kD protein, whereas CYP3A4 migrates as a 52.0-kD protein. The human CYP3A subfamily, CYP3A4, CYP3A5, CYP3A7 and CYP3A43, is one of the most versatile of the biotransformation systems that facilitate the elimination of drugs (37% of the 200 most frequently prescribed drugs in the U.S.).
CYP3A4 and CYP3A5 together account for approximately 30% of hepatic cytochrome P450, and approximately half of medications that are oxidatively metabolized by P450 are CYP3A substrates. Both CYP3A4 and CYP3A5 are expressed in liver and intestine, with CYP3A5 being the predominant form expressed in extrahepatic tissues.
Selective inhibition and therapeutic relevance
The (wild-type) CYP3A enzymes have traditionally been thought of as functionally redundant, distinguishable mostly by expression patterns. Since CYP3A5 is almost always expressed at significantly lower levels than CYP3A4, an understanding of its clinical significance was limited. Most studies suggesting any non-overlapping metabolic functions apart from CYP3A4 were limited to small differences in metabolites produced from drugs which themselves were still substrates of CYP3A4. However, in 2016 it was found that CYP3A5 mediated acquired drug resistance in pancreatic ductal adenocarcinoma, a type of pancreatic cancer
Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
. This not only showed a context of selective CYP3A5 expression, but also demonstrated a therapeutic need for selective CYP3A5 inhibition and hinted that its metabolic role was not completely redundant with CYP3A4. Indeed, chemical tools would soon after be developed which could demonstrate and probe the selective CYP3A5 metabolic activity.
In 2020, Wright et al. reported the first CYP3A5-selective inhibitor Clobetasol Propionate
Clobetasol propionate is a corticosteroid used to treat skin conditions such as eczema, contact dermatitis, seborrheic dermatitis, and psoriasis. It is applied to the skin as a cream, ointment, or shampoo. Use should be short term and only if ot ...
. The study demonstrated a strong inhibition of CYP3A5 and showed its high selectivity over other CYP3A enzymes including CYP3A4. It was proposed that Clobetasol Propionate differentially occupied the binding site of CYP3A5 compared to CYP3A4 (which would later become validated with subsequent studies).
Allele distribution
The CYP3A5 gene has several functional variants, which vary depending on ethnicity. The CYP3A5*1 allele is associated with a normal metabolization of medication. It is most common among individuals native to Sub-Equatorial Africa
Southern Africa is the southernmost subregion of the African continent, south of the Congo and Tanzania. The physical location is the large part of Africa to the south of the extensive Congo River basin. Southern Africa is home to a number of ...
, though the mutation also occurs at low frequencies in other populations. The CYP3A5*3 allele is linked with a poor metabolization of medication. It is near fixation in Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
, and is likewise found at high frequencies in West Asia
Western Asia, West Asia, or Southwest Asia, is the westernmost subregion of the larger geographical region of Asia, as defined by some academics, UN bodies and other institutions. It is almost entirely a part of the Middle East, and includes Ana ...
and Central Asia
Central Asia, also known as Middle Asia, is a subregion, region of Asia that stretches from the Caspian Sea in the west to western China and Mongolia in the east, and from Afghanistan and Iran in the south to Russia in the north. It includes t ...
, as well as among Afro-Asiatic (Hamitic-Semitic) speaking populations in North Africa
North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
and the Horn of Africa
The Horn of Africa (HoA), also known as the Somali Peninsula, is a large peninsula and geopolitical region in East Africa.Robert Stock, ''Africa South of the Sahara, Second Edition: A Geographical Interpretation'', (The Guilford Press; 2004), ...
. Additionally, the mutation occurs at moderate-to-high frequencies in South Asia
South Asia is the southern subregion of Asia, which is defined in both geographical and ethno-cultural terms. The region consists of the countries of Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka.;;;;;;;; ...
, Southeast Asia
Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia, South-eastern Asia or SEA, is the geographical United Nations geoscheme for Asia#South-eastern Asia, south-eastern region of Asia, consistin ...
and East Asia
East Asia is the eastern region of Asia, which is defined in both geographical and ethno-cultural terms. The modern states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. China, North Korea, South Korea and ...
, and at low frequencies in Sub-Equatorial Africa.
Global distribution of the CYP3A5 alleles:
Interactive pathway map
See also
* Cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
References
Further reading
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External links
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{{Cytochrome P450