Zonation of cytochrome P450 expression, drug metabolism and toxicity in liver

Abstract

1. In this brief review, current concepts on the zonated expression of liver genes involved in phase I and phase II drug metabolism will be presented. 2. It is now clear that the P450 isoforms involved in drug activation and steroid metabolism exhibit a particularly prominent zonation, with high expression and preferential induction in hepatocytes of the perivenous region. 3. In comparison, among the phase II enzymes, the perivenous dominance of glutathione transferases and UDP-glucuronyltransferases is less prominent, and glutathione peroxidase displays an opposite, periportally dominated pattern. 4. The factors regulating the zonated expression of these and other liver genes are poorly known. We have observed that pituitary-dependent hormones, particularly growth hormone, extinguish the periportal (upstream) expression of several CYP forms (CYP2B1/2 and CYP3A1/2). However, the zonation of other CYP forms (CYP2A, CYP2E1, CYP 2C11 and CYP 2C12) is less affected, suggesting that hormonal factors are important, but that the zonation of each P450 form is orchestrated by a different set of factors. 5. Because many hepatotoxins cause zone-specific damage, further unravelling the factors governing zonal expression of phase I and phase II enzymes will be necessary to clarify how drug-specific patterns of liver damage arise.