CYTOCHROME P-450 3A4: Regulation and Role in Drug Metabolism

Abstract

▪ Abstract  Cytochrome P-450 (P-450) 3A4 is the most abundant P-450 expressed in human liver and small intestine. P-450 3A4 contributes to the metabolism of approximately half the drugs in use today, and variations in its catalytic activity are important in issues of bioavailability and drug-drug interactions. The gene is known to be inducible by barbiturates, glucocorticoids, and rifampicin in humans and in isolated hepatocytes, although the mechanism remains unclear. The 5′-untranslated region includes putative basal transcription element, hepatocyte nuclear factor, p53, AP-3, glucocorticoid regulatory element, pregnane X receptor, and estrogen receptor element sequences. Recently, the GRE element has been shown to act in a classic glucocorticoid response. Several issues remain to be resolved regarding the catalytic activity of the P-450 3A4 protein, including rate-limiting steps and the need for cytochrome b5, divalent cations, and acidic phospholipid systems for optimal activity. Another issue involves the basis of the homotropic and heterotropic cooperativity seen with the enzyme. The in vivo significance of these findings remains to be further established. In addition to more basic studies on P-450 3A4, several areas of practical interest to the pharmaceutical industry require development.