Effect of treatment with pyrazine and some derivatives on cytochrome P450 and some enzyme activities in rat liver.

Abstract

1. The effect of pyrazine and three pyrazine derivatives, namely (methylthio) methylpyrazine (MTMP), 5, 6, 7, 8-tetrahydroquinoxaline (CHP) and 5-methyl-6, 7-dihydro-5'-cyclopentapyrazine (CPP), on hepatic peroxisomal and microsomal enzyme activities have been studied in male Sprague-Dawley rats. MTMP (0.25-2 mmol/kg per day) and the other compounds (1 mmol/kg/day) were administered by i.p. injections for 3 days. 2. None of the test compounds appeared to be peroxisome proliferators as there was no marked effect on hepatic palmitoyl-CoA oxidation, and neither pyrazine nor MTMP induced microsomal lauric acid 12-hydroxylase. 3. In contrast, all four compounds induced hepatic microsomal cytochrome P450-dependent enzyme activities. MTMP induced the metabolism of several mixed-function oxidase substrates including, 7-pentoxyresorufin, 7-benzoxyresorufin, benzphetamine, 4-nitrophenol and aniline, whereas pyrazine induced the metabolism of fewer substrates but including 4-nitrophenol and aniline. 4. By Western immunoblotting MTMP was found to increase levels of CYP2B1 and CYP3A isoenzymes, whereas pyrazine increased CYP2E1. 5. Thus, while pyrazine appears to be mainly a CYP2E inducer, MTMP is a mixed inducer of cytochrome P450 isoenzymes in the CYP2B, CYP3A and CYP2E subfamilies. CPP is probably a CYP2E inducer in rat liver, whereas CHP appears to be a mixed inducer of cytochrome P450 isoenzymes in the CYP2B, CYP3A and CYP2E subfamilies.