CYP4B1: an enigmatic P450 at the interface between xenobiotic and endobiotic metabolism

Abstract

CYP4B1 belongs to the mammalian CYP4 enzyme family that also includes CYP4A, 4F, 4V, 4X, and 4Z subfamilies. CYP4B1 shares with other CYP4 proteins a capacity to omega-hydroxylate medium-chain fatty acids, which may be related to an endogenous role for the enzyme. CYP4B1 also participates in the metabolism of certain xenobiotics that are protoxic, including valproic acid, 3-methylindole, 4-ipomeanol, 3-methoxy-4-aminoazobenzene, and numerous aromatic amines. Although these compounds have little in common structurally or chemically, their metabolism by CYP4B1 leads to tissue-specific toxicities in several experimental animals. The bioactivation capabilities of rabbit CYP4B1 have also attracted attention in the cancer community and form the basis of a potential therapeutic strategy involving prodrug activation by the CYP4B1 transgene. The metabolic capabilities of human CYP4B1 are less clear due to difficulties in heterologous expression and existence of alternatively spliced products. Also, many CYP4B1 enzymes covalently bind their heme, a posttranslational modification unique to the CYP4 family of P450s, but common to the mammalian peroxidases. These varied characteristics render CYP4B1 an interesting and enigmatic investigational target.