Bioactivation of the mushroom hydrazine, agaritine, to intermediates that bind covalently to proteins and induce mutations in the Ames test |
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Authors: | Walton K; Coombs MM; Catterall FS; Walker R; Ioannides C |
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Institution: | School of Biological Sciences, University of Surrey, Guildford, UK. |
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Abstract: | The present study was undertaken to establish whether liver and kidney
enzyme systems, from rat and mouse, have the potential to metabolise and
bioactivate agaritine, beta-N-(gamma-L(+)glutamyl)-4-
(hydroxymethyl)phenylhydrazine, the most abundant hydrazine present in the
edible mushroom Agaricus bisporus. Agaritine was weakly mutagenic, in the
absence of an activation system, in Salmonella typhimurium strain TA104.
Rat kidney homogenates, characterised by high gamma- glutamyl
transpeptidase activity, enhanced the mutagenic response. In contrast,
hepatic microsomes, having very low gamma-glutamyl transpeptidase activity,
did not influence the mutagenicity of agaritine. However, hepatic
microsomes could further potentiate the mutagenic response induced by the
kidney. Agaritine was a good substrate for purified gamma-glutamyl
transpeptidase, being converted to a major metabolite,
4-(hydroxymethyl)phenylhydrazine, formed as a result of the loss of the
glutamyl moiety. Kidney homogenates from the rat and mouse also catalysed
this reaction, the former being the more effective. Metabolism of agaritine
was suppressed by serine-borate, an inhibitor of gamma-glutamyl
transpeptidase. Kidney homogenates from rat and mouse could metabolise
agaritine to intermediate(s) that bound covalently to proteins, with the
rat preparations being the more effective; covalent binding was inhibited
by glutathione. In contrast, hepatic preparations alone were ineffective in
producing such covalent binding but did further increase the covalent
binding mediated by the kidney preparations. It is concluded that rat and
mouse kidney homogenates catalyse the removal of the glutamyl group from
agaritine to yield the reactive free hydrazine, which is further converted
to the highly reactive diazonium ion by hepatic microsomes.
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