Induction of rat hepatic cytochrome P4501A and P4502B by the methoxsalen.

Abstract

The effect of methoxsalen, the inhibitor of the hepatic mixed function oxidase, on the expression of liver cytochrome P450s was examined in rats. Administration of methoxsalen to rats significantly increased the hepatic content of P450 and activities of microsomal ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), pentoxyresorufin O-dealkylase (PROD), a representative activity of P4501A1, P4501A2 and P4502B1/2, respectively, in a dose-dependent manner. In contrast, there was no effect on the P4502E1 catalyzed aniline hydroxylase. In the time-course experiment, methoxsalen exhibited a biphasic effect on EROD, MROD, and PROD activities, an initial inhibitory phase was followed by a phase of induction following a single treatment. Immunoblot analysis using anti-rat liver P4501A and P4502B revealed that increase in the apoprotein levels of P4501A1/2 and P4502B1/2 by methoxsalen was consistent with those in enzyme activity levels. Levels of mRNA of P4501A1/2 and P4502B1/2 were also increased by methoxsalen in Northern blot analysis. These results demonstrated that methoxsalen acts as an inducer of the hepatic microsomal mixed function oxidase; selective induction of P4501A and P4502B families involved increases in mRNA levels.