Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.

Quick Facts Identifiers, Aliases ...

CYP3A5
Identifiers
Aliases	CYP3A5, CP35, CYPIIIA5, P450PCN3, PCN3, cytochrome P450 family 3 subfamily A member 5
External IDs	OMIM: 605325; MGI: 106099; HomoloGene: 133568; GeneCards: CYP3A5; OMA:CYP3A5 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q22.1 Start 99,648,194 bp[1] End 99,679,998 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 G2|5 85.17 cM Start 145,373,119 bp[2] End 145,406,533 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa right lobe of liver gallbladder duodenum rectum mucosa of sigmoid colon body of pancreas buccal mucosa cell pylorus mucosa of transverse colon Top expressed in hepatobiliary system liver sexually immature organism duodenum muscle sensory nervous system sensory organ retina muscle tissue central nervous system More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding oxidoreductase activity oxygen binding aromatase activity oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen metal ion binding monooxygenase activity estrogen 16-alpha-hydroxylase activity Cellular component organelle membrane endoplasmic reticulum membrane intracellular membrane-bounded organelle endoplasmic reticulum membrane Biological process xenobiotic metabolic process alkaloid catabolic process oxidative demethylation lipid hydroxylation steroid metabolic process estrogen metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1577 13114 Ensembl ENSG00000106258 ENSMUSG00000038656 UniProt P20815 Q64481 RefSeq (mRNA) NM_000777 NM_001190484 NM_001291829 NM_001291830 NM_007820 RefSeq (protein) NP_000768 NP_001177413 NP_001278758 NP_001278759 NP_031846 Location (UCSC) Chr 7: 99.65 – 99.68 Mb Chr 5: 145.37 – 145.41 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Close

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]

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

• Cytochrome P450