Liver Cytochrome P450 Metabolism of Endogenous Steroid Hormones, Bile Acids, and Fatty Acids

Abstract

Cytochromes P450 metabolize a large variety of lipophilic compounds that often have little or no structural similarity. Common cytochrome P450 substrates include both xenobiotics (drugs, carcinogens, environmental pollutants, and other chemicals) and endogenous metabolites (steroids, fatty acids, prostaglandins, etc.). As shown in Fig. 1, the major sites of cytochrome P450 action in mammalian metabolism are reactions connected to sterol metabolism. Notable exceptions include the ω and ω-1 oxidation of fatty acids (catalyzed by cytochrome P450 family 4) and the oxidation of ethanol and other low molecular weight compounds (cytochrome P450 subfamily 2E). Both the biosynthesis of cholesterol (lanosterol demethylase) and the conversion of cholesterol into its metabolites require the participation of multiple cytochromes P450, each of which catalyzes a distinct hydroxylation reaction, some of which lead to carbon-carbon cleavage (desmolase activity; e.g., cytochrome P450 11 A). Quantitatively most important for cholesterol catabolism is the pathway leading to bile acids, which involves several distinct cytochrome P450 enzymes, including cholesterol 7α-hydroxylase (cytochrome P450 family 7), which catalyzes the first, and rate-limiting, step; a 27-hydroxylation (cytochrome P450 family 27) that initiates side chain oxidation, and a 12α-hydroxylation that leads to cholic acid formation.