Comutagenesis-III. In vitro metabolism of 2-amino3-methylpyridine : the effect of various potential inhibitors, activators and inducers

Abstract

1. The effects of various potential inhibitors,activators and inducers on the metabolism of the comutagen 2-amino- 3-methylpyridine(2A3MP) by rabbit hepatic microsomes and S9 supernatants have been studied. 2. The 1-N-oxidation of 2A3MP to 2-amino- 3-methylpyridine- 1-N-oxide (2A3MPNO) was inhibited by 2,4-dichloro- 6-phenylphenoxyet hylamine (DPEA), 2-diethylaminoethyl- 2,2-diphenylvalerat e (SKF 525-A) and n-octylamine. 3. The C-oxidation products of 2A3MP, i.e. 2-amino- 3-hydroxymethylpy ridine (2A3HMP) and 2-amino- 3-methyl- 5-hydroxypyridine (2A3M5HP), were also inhibited by these compounds. 4. Pretreatment of animals with phenobarbitone (PB) resulted in an increase in the production of 2A3MPNO and 2A3HMP, whereas β-naphthoflavone (BNF) pretreatment had a greater effect on the formation of 2A3M5HP. 5. Pretreatment with pyridine or pyrazine also had an appreciable effect on the formation of 2A3HMP. 6. It is suggested that different cytochrome P450 isozymes are responsible for the metabolic profile of 2A3MP. CYP2B was involved in the N-oxidation; 2E and or 2B in the formation of 2A3HMP, and 3A and or 1A in the formation of 2A3M5HP.