Modulation of the expression of constitutive rat hepatic cytochrome P450 isozymes by 5-fluorouracil

Abstract

The objective of this study was to determine the effects of 5-fluorouracil (5FU) on the expression of individual cytochrome P450 (CYP) isozymes in rat liver at the catalytic activity and apoprotein levels. Male Fischer 344 rats (9 to 10) weeks old) received a single intraperitoneal injection of 5FU (120 mg/kg) or vehicle. Rats were euthanized 1, 2, 7, or 14 days following drug administration. Hepatic microsomes were isolated and used for determination of spectral CYP and heme content and steroid hydroxylation activity, and immunoblot analysis of CYP apoproteins. 5FU treatment did not alter the levels of total microsomal CYP and heme. The major male-specific CYP isozyme, CYP2C11, was downregulated by 5FU treatment, as revealed by a significant decrease in CYP2C11 immunoreactive protein and catalytic activity (progesterone 2 alpha-hydroxylase) levels at day 14. Members of the CYP3A subfamily also appeared to be modulated by 5FU treatment in a complex manner. Two days following 5FU exposure, CYP3A immunoreactive protein was increased compared with vehicle control; however, 7 days after treatment, both CYP3A immunoreactivity and catalytic activity (progesterone 6 beta-hydroxylase) were suppressed by 5FU. 5FU appears to modulate the expression of constitutive CYP isozymes in the liver of male rats. The modulation of the catalytic activity of CYP2C11 and CYP3A by 5FU appears to be due to changes in the expression of the corresponding proteins.