Prostaglandin H synthase-dependent mutagenic activation of heterocyclic aromatic amines of the IQ-type

Abstract

Microsomes from ram seminal vesicles known as a rich source of prostaglandin H synthase (PHS) activate the food mutagen IQ (2-amino-3-methylimidazo[4,5-f]quinoline) to (a) product(s) mutagenic in Salmonella typhimurium TA98. The activation is dependent on the PHS cofactor arachidonic acid and is strongly inhibited by the PHS inhibitor indomethacin. In this system, the mutagenic potency of IQ is 22 and 110 times higher than that of 2-aminofluorene and benzidine, respectively. The high mutagenic potency of IQ observed previously with mono-oxygenase activation is thus extended to the PHS system. The mutagenic activity produced by PHS increases for 4 h; this contrasts with the relatively short lifetime of the activity produced by mono-oxygenase and suggests that different agents are involved in the two processes. The PHS-mediated mutagenic activity of IQ is strongly dependent on the bacterial O-acetyltransferase which is defective in strain TA98/1,8-DNP6. Further, the responses of the strains TA1978 and TA1538 indicate that the mutagenic activity is dependent on lack of the bacterial DNA excision repair and independent of the plasmid pkM101 coded error-prone DNA repair system. Structural analogs of IQ without a methyl group on the imidazole ring and with a naphthalene instead of the quinoline ring show greatly diminished PHS-mediated mutagenic activity. The strain response pattern and structure-activity relationships similar to those found with mono-oxygenase activation of IQ and thus indicate a basic similarity of the IQ activation via PHS with that via mono-oxygenase. It is hypothesized that PHS may activate carcinogenic heterocyclic aromatic amines in vivo.