Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.
Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.
CYP3A5 encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the prostate and the liver. [5] 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). [5]
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. [6]
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. [5] 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. [7] 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. [8] ).
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. [9] Both CYP3A4 and CYP3A5 are expressed in liver and intestine, with CYP3A5 being the predominant form expressed in extrahepatic tissues. [9]
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. [10] However, in 2016 it was found that CYP3A5 mediated acquired drug resistance in pancreatic ductal adenocarcinoma, a type of pancreatic cancer. [11] 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. [12] 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). [13]
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, 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, and is likewise found at high frequencies in West Asia and Central Asia, as well as among Afro-Asiatic (Hamitic-Semitic) speaking populations in North Africa and the Horn of Africa. Additionally, the mutation occurs at moderate-to-high frequencies in South Asia, Southeast Asia and East Asia, and at low frequencies in Sub-Equatorial Africa. [14] [15]
Global distribution of the CYP3A5 alleles: [15]
| Population | CYP3A5*1 | CYP3A5*3 | CYP3A5*6 | CYP3A5*7 |
|---|---|---|---|---|
| Adygei | 12% | 88% | ||
| Afar | 35% | 65% | 18% | 0% |
| African Americans | 63% | 37% | 12% | 21% |
| Algerians (North) | 19% | 81% | 5% | 1% |
| Amhara | 33% | 67% | 15% | 0% |
| Anatolian Turks | 9% | 91% | 0% | 0% |
| Armenians (South) | 5% | 95% | 0% | 0% |
| Asante | 89% | 11% | 22% | 7% |
| Ashkenazi Jews | 3% | 97% | 0% | 0% |
| Balochi | 20% | 80% | ||
| Bantu (Kenya) | 83% | 17% | ||
| Bantu (South Africa) | 74% | 26% | 18% | 10% |
| Bantu (Uganda) | 96% | 4% | 22% | 21% |
| Basques (French) | 4% | 96% | ||
| Bedouin (Israel) | 17% | 83% | ||
| Berbers (Morocco) | 20% | 80% | 4% | 1% |
| Biaka Pygmies | 89% | 11% | ||
| Brahui | 12% | 88% | ||
| Britons (England and Scotland) | 35% | 65% | 0% | |
| Bulsa | 81% | 19% | 16% | 13% |
| Burusho | 22% | 78% | ||
| Cameroonian (Lake Chad) | 76% | 24% | 32% | 7% |
| Canadian Caucasians | 7% | 93% | 0% | 0% |
| Chagga | 74% | 26% | 14% | 9% |
| Chewa | 85% | 15% | 16% | 17% |
| Chinese | 25% | 75% | 0% | |
| Chinese (Denver, Colorado) | 25% | 75% | ||
| Colombians | 15% | 85% | ||
| Colombians (Medellian) | 48% | 52% | 2% | |
| Congolese (Brazzaville) | 80% | 20% | 12% | 9% |
| Dai | 45% | 55% | ||
| Druze | 8% | 92% | ||
| Daur | 15% | 85% | ||
| East Asian | 31% | 69% | 0% | 0% |
| European | 2% | 98% | 0% | 0% |
| Finns | 45% | 55% | 0% | |
| French | 8%-9% | 91%-92% | 0% | 0% |
| Gabonese | 79% | 21% | 19% | 19% |
| Gambians | 79% | 21% | 20% | 12% |
| Germans | 7% | 93% | ||
| Gujarati (Houston, Texas) | 25% | 75% | ||
| Han | 25% | 75% | ||
| Han (Beijing) | 28% | 72% | 0% | |
| Han (Southern) | 47% | 53% | 0% | |
| Hazara | 25% | 75% | ||
| Hezhen | 15% | 85% | ||
| Hispanic | 25% | 75% | 0% | 0% |
| Iberians | 39% | 61% | 0% | |
| Igbo | 87% | 13% | 18% | 9% |
| Indians | 41% | 59% | 0% | |
| Italians (Bergamo) | 18% | 82% | ||
| Italians (Sardinia) | 5% | 95% | ||
| Italians (Tuscany) | 5%-6% | 94%-95% | 0.5% | |
| Japanese | 23% | 77% | 0% | |
| Japanese (Tokyo) | 26% | 74% | 0.004% | |
| Kalash | 24% | 76% | ||
| Karitiana | 23% | 77% | ||
| Kasena | 78% | 22% | 17% | 13% |
| Khmer | 27% | 73% | ||
| Koreans | 19% | 81% | 0% | |
| Kotoko | 73% | 27% | 23% | 5% |
| Lahu | 25% | 75% | ||
| Lemba | 87% | 13% | 25% | 15% |
| Lomwe | 83% | 17% | 22% | 11% |
| Luhya (Webuye, Kenya) | 86% | 14% | 26% | |
| Maale | 51% | 49% | 15% | 1% |
| Maasai (Kinyawa, Kenya) | 51% | 49% | 14% | |
| Makrani | 14% | 86% | ||
| Malay | 39% | 61% | 0% | |
| Malawians | 79% | 21% | 14% | 14% |
| Mandenka | 69% | 31% | ||
| Manjak | 79% | 21% | 23% | 7% |
| Maya | 29% | 71% | ||
| Mayo Darle | 73% | 27% | 25% | 6% |
| Mbuti Pygmies | 93% | 7% | ||
| Melanesians | 18% | 82% | ||
| Mestizo (El Salvador and Nicaragua) | 24% | 76% | ||
| Mestizo (Ecuador) | 12% | 88% | ||
| Mexicans (Los Angeles) | 25% | 75% | 2% | |
| Miaozu | 35% | 65% | ||
| Mongola | 35% | 65% | ||
| Mozabite | 16% | 84% | ||
| Naxi | 28% | 72% | ||
| Ngoni | 89% | 11% | 33% | 6% |
| North American Caucasians | 9% | 90% | ||
| Orogen | 10% | 90% | ||
| Orcadians | 16% | 84% | ||
| Oromo | 35% | 65% | 14% | 0% |
| Papuans | 21% | 79% | ||
| Palestinians | 18% | 82% | ||
| Pathan | 12% | 88% | ||
| Pima | 54% | 46% | ||
| Puerto Ricans | 56% | 44% | 5% | |
| Russians | 8% | 92% | ||
| San (Namibia) | 93% | 7% | ||
| Sena | 84% | 16% | 23% | 16% |
| Sephardi Jews | 11% | 89% | 0% | 0% |
| She | 45% | 55% | ||
| Shewa Arabs | 60% | 40% | 22% | 7% |
| Shona | 22% | 78% | 22% | 10% |
| Sindhi | 18% | 82% | ||
| Somie (Cameroonian Grassfields) | 77% | 23% | 18% | 10% |
| Southern Sudanese | 76% | 24% | 33% | 3% |
| Spaniard | 9% | 91% | ||
| Sudanese (Northern) | 40% | 60% | 11% | 0% |
| Sudanese (Kordofan) | 55% | 45% | 20% | 2% |
| Surui | 17% | 83% | ||
| Swedes | 7% | 93% | 0% | 0% |
| Tanzanians | 81% | 19% | 19% | 12% |
| Tu | 10% | 90% | ||
| Tujia | 35% | 65% | ||
| Tunisian | 19% | 81% | 1% | 0% |
| Uygur | 5% | 95% | ||
| Wolof | 73% | 27% | 18% | 9% |
| Xibo | 22% | 78% | ||
| Yao | 82% | 18% | 13% | 9% |
| Yakuts | 10% | 90% | ||
| Yemeni (Hadramaut) | 15% | 85% | 3% | 1% |
| Yemeni (Sena and Msila) | 42% | 58% | 12% | 3% |
| Yizu | 20% | 80% | ||
| Yoruba | 83%-94% | 6%-17% | 17%-75% | 0% |
| Zimbabweans (Mposi) | 84% | 16% | 16% | 19% |
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.
Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.
Cytochrome P450 2A6 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and cotinine. It is also involved in the metabolism of several pharmaceuticals, carcinogens, and a number of coumarin-type alkaloids. CYP2A6 is the only enzyme in the human body that appreciably catalyzes the 7-hydroxylation of coumarin, such that the formation of the product of this reaction, 7-hydroxycoumarin, is used as a probe for CYP2A6 activity.
Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.
Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.
Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.
In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the NR1I2 gene.
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.
CYP3A7 is an enzyme belonging to the cytochrome P450 family. It is 503 amino acids in size and shares 87% of its sequence with CYP3A4. It carries out a similar role in fetuses that CYP3A4 serves in adults. The gene location is 7q22.1.
Cytochrome P450 4B1 is a protein that in humans is encoded by the CYP4B1 gene.
Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice.
Cytochrome P450 4F2 is a protein that in humans is encoded by the CYP4F2 gene. This protein is an enzyme, a type of protein that catalyzes chemical reactions inside cells. This specific enzyme is part of the superfamily of cytochrome P450 (CYP) enzymes, and the encoding gene is part of a cluster of cytochrome P450 genes located on chromosome 19.
Cytochrome P450 2A13 is a protein that in humans is encoded by the CYP2A13 gene.
Cytochrome P450 3A43 is a protein that in humans is encoded by the CYP3A43 gene.
Cytochrome P450 2F1 is a protein that in humans is encoded by the CYP2F1 gene.
CYP39A1 also known as oxysterol 7-α-hydroxylase 2 is a protein that in humans is encoded by the CYP39A1 gene.
CYP26C1 is a protein which in humans is encoded by the CYP26C1gene.
CYP2A7 is a protein that in humans is encoded by the CYP2A7 gene.
{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)