Glutathione transferase-mediated and non-enzymatic activation and detoxication of the N-hydroxy derivative of Trp-P-2, a potent pyrolysate promutagen

Abstract

1. Glutathione (GSH) transferase-mediated and non-enzymatic activation and detoxication of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) were studied in vitro. N-OH-Trp-P-2 is an active metabolite of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), a mutagenic and carcinogenic heterocyclic amine.

2. The enzymatic GSH conjugation with N-OH-Trp-P-2 was catalysed by rat-liver GSH transferase and a rat-liver cytosol fraction to form three conjugates (CH-1, CH-2 and CH-3).

3. The mutagenicities of the GSH conjugates were studied by using Salmonella typhimurium TA98 as the tester strain.

4. The GSH conjugates except for CH-3 were completely detoxicated products, but CH-3 was found to be a more potent mutagen than N-OH-Trp-P-2.

5. The mutagenicity of CH-3 seemed to be due to the direct action of the conjugate, but not to N-OH-Trp-P-2 formed from it.