Regulation of liver-specific steroid metabolizing cytochromes P450: Cholesterol 7α-hydroxylase, bile acid 6β-hydroxylase, and growth hormone-responsive steroid hormone hydroxylases

Abstract

The hydroxylation of cholesterol, bile acids, and steroid hormones by liver cytochrome P450 (CYP) enzymes proceeds with a high degree of regiospecificity, and contributes to both biosynthetic and catabolic pathways of sterol metabolism. CYP 7-catalyzed cholesterol 7α-hydroxylation, a key control point of bile acid biosynthesis, is regulated at a pretranslational step, probably transcription initiation, by multiple factors, including liver bile acid and cholesterol levels, thyroid hormone status, and diurnal rhythm. Hydrophobic bile acids, such as lithocholic acid, are converted to less cholestatic derivatives by 6β-hydroxylation carried out by CYP 3A P450s, which also catalyze steroid hormone 6β-hydroxylation reactions. Complex, gender-dependent developmental patterns characterize the expression of steroid 5α-reductase and several rat liver steroid hydroxylase CYPs. Multiple pituitary-dependent factors regulate the expression of these enzymes; of greatest importance are the gonadal steroids and the sex-dependent secretory patterns of growth hormone (GH) that they impart. The continuous presence of GH in circulation, a characteristic of adult female rats, positively regulates expression of the female-specific steroid disulfate 15β-hydroxylase CYP 2C12, while expression of the male-specific steroid 16α- and 2α-hydroxylase CYP 2C11 is stimulated by the intermittent pituitary secretion of GH that occurs in adult male rats. Intermittent GH can stimulate CYP 2C11 gene expression even when the hormone presents to the hepatocyte at a non-physiological pulse amplitude, duration, and frequency, provided that an interpulse interval of no GH (obligatory recovery period) is maintained for at least 2.5 h. GH regulates the expression of the CYP 2C11 and CYP 2C12 genes at the level of transcription initiation. This process is probably mediated by sex-dependent and GH-regulated protein-DNA interactions, such as those observed in the 5′-flank of the CYP 2C12 gene. Thyroid hormone is a second major regulator of liver steroid hydroxylase P450 activity. It regulates these enzymes directly, at a pretranslational step, and indirectly, through its stimulation of pituitary GH secretion and by its positive effects on the expression of the flavoenzyme NADPH- P450 reductase, which catalyzes electron transfer that is obligatory for all microsomal steroid hydroxylation reactions.