The rat cytochrome P450 C‐M/F (CYP2D) subfamily: Constitutive P450 isozymes in male and female

Abstract

Cytochrome P450 (CYP) isozymes have been cloned from various tissues and species and form the cytochrome P450 superfamily. We have isolated cytochrome P450 C‐M/F, which we regard as a major form of the constitutive cytochrome P450 isozyme. Cytochrome P450 C‐M/F was highly active in the 2‐ and 16α‐hydroxylation of estrogens, as well as in the N‐demethylation of ethyl‐morphine and benzphetamine. It was essentially uninducible by phenobarbital, 3‐methylcholan‐threne or β‐naphthoflavone. Immunochemical studies demonstrated the presence of cytochrome P450 C‐M/F in the liver of male and female rats and in the kidney of male rats. This is consistent with P450 C‐M/F activity towards estrogens, since they are metabolized in the liver and kidney and excreted into the urine. Highly similar genes were identified by immunoscreening, and comprised the CYP2D sub‐family. Five genes—CYP2D1, CYP2D2, CYP2D3, CYP2D4 and CYP2D5—have been isolated from rats. In spite of the high similarity, there is an obvious difference in substrate specificity between even the most similar isozymes. Among allelic variants reported for CYP2D1 and CYP2D2, P450IID1v is a mutant with decreased activity specifically towards bufuralol, due to a single amino acid substitution. Biochemical studies have demonstrated enzyme activities of CYP2D1 and CYP2D2 isozymes, while those of CYP2D3, CYP2D4 and CYP2D5 remain unknown. It is suggested that CYP2D isozymes play a role in maintaining homeostasis of the organism since they are constitutively expressed in the livers of both sexes and in the kidneys of males. Understanding their endogenous substrates should help to clarify their roles.