Bioactivation of mushroom hydrazines to mutagenic products by mammalian and fungal enzymes.
Agaritine (N2-[L-(+)-glutamyl]-4-(hydroxymethylphenyl)hydrazine), the principal hydrazine found in the edible mushroom Agaricus bisporus, as well as the N'-acetyl derivative of 4-(hydroxymethyl)phenylhydrazine and 4-(hydroxymethyl)benzene diazonium ion, as the tetraborate salt, considered as the putative proximate and ultimate carcinogens of agaritine, were all synthesised chemically. The mutagenicity of these compounds and of 4-hydrazinobenzoic acid, a precursor of agaritine biosynthesis in mushroom, was investigated in the Ames test, using Salmonella typhimurium strain TA104, in the absence and in the presence of either mushroom tyrosinase or rat hepatic cytosol as activation systems. In the absence of an activation system the diazonium ion was clearly the most mutagenic of the four compounds studied. When tyrosinase was used as activation system, the mutagenicity of N'-acetyl-4-(hydroxymethyl)phenylhydrazine was enhanced; glutathione and superoxide dismutase markedly suppressed the mutagenic response. When the mutagenicity of the four compounds was evaluated in the presence of rat hepatic cytosol, an increase was seen only in the case of N'-acetyl-4-(hydroxymethyl)phenylhydrazine; this was shown to be due to deacetylation releasing the more mutagenic free hydrazine. Collectively, the above data are compatible with an activation of agaritine that involves an initial loss of the gamma-glutamyl group followed by microsomal oxidation of the free hydrazine to generate the diazonium ion. Also of interest is the observation that mushroom tyrosinase can convert N'-acetyl-4-(hydroxymethyl)phenylhydrazine to mutagenic product(s); whether these products contribute to the mutagenicity of mushroom extracts remains to be established.
Walton
K
K
School of Biological Sciences, University of Surrey, Guildford, UK.
Coombs
M M
MM
Walker
R
R
Ioannides
C
C
D000364:Agaricus / Q000737:chemistry*; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006834:Hydrazines / Q000378:metabolism* / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010659:Phenylhydrazines / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D001140:Aroclors; D001565:Benzoates; D006834:Hydrazines; D009153:Mutagens; D010659:Phenylhydrazines; D020111:Chlorodiphenyl (54% Chlorine); C053198:4-hydrazinobenzoic acid; D014442:Monophenol Monooxygenase; C015654:agaritine