The CYP3A subfamily includes the most abundantly expressed CYP450s in the human liver and intestine (extrahepatic metabolism).
Although CYP3A4 is responsible for approximately two-thirds of CYP3A-mediated drug metabolism, the other minor isoforms (CYP3A5,
CYP3A7, and CYP3A43) also contribute. The CYP3A5 is the best studied of the minor CYP3A isoforms. Approximately 20% of human livers express CYP3A5. The expression of CYP3A5
shows interethnic differences, with the wild-type CYP3A5*1 allele being more common in Africans than in Caucasians and Asians. In
individuals who express CYP3A5, 17 to 50% of the total hepatic CYP3A is this isoform. Additionally, CYP3A5 also is expressed in a range
of extrahepatic tissues and is inducible via pregnane X receptor. Both CYP3A4 and CYP3A5 exhibit significant overlap in substrate
specificity but can differ in catalytic activity and regioselectivity. Results from a comparison of CYP3A4 and CYP3A5 enzyme kinetics
indicate that CYP3A5 has different enzymic characteristics from CYP3A4 in some CYP3A-catalyzed reactions. The enzyme kinetics for
CYP3A5 suggest a faster substrate turnover than with CYP3A4.
Biologische Funktion
Approximately one-third of the total CYP450 in the liver and two-thirds in the intestine is CYP3A4. This isoform is responsible for the
metabolism of more than one-third of the clinically important drugs. The CYP3A4 is expressed in the intestine, lung, placenta, kidney,
uterus, and brain and is glucocorticoid inducible. The CYP3A7 is predominantly expressed in fetal liver (~50% of total fetal CYP450
enzymes) but also is found in some adult livers and extrahepatically. The CYP3A7 has a specific role in hydroxylation of retinoic acid,
16α-hydroxylation of steroids, and hydroxylation of allylic and benzylic carbons and, therefore, is of relevance both to normal development and to carcinogenesis. The most recently discovered CYP3A isoform is
CYP3A3. In addition to a low level of expression in liver, it is expressed in prostate and testis. Its substrate specificity currently is unclear.
Polymorphisms predicting absence of active enzyme have been identified.
