EFFECT OF TREATMENT WITH PYRAZINE AND SOME DERIVATIVES ON CYTOCHROME-P450 AND SOME ENZYME-ACTIVITIES IN RAT-LIVER

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-5H-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.