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  • Title: Prostaglandin hydroperoxidase-dependent activation of heterocyclic aromatic amines.
    Author: Petry TW, Josephy PD, Pagano DA, Zeiger E, Knecht KT, Eling TE.
    Journal: Carcinogenesis; 1989 Dec; 10(12):2201-7. PubMed ID: 2512013.
    Abstract:
    Heterocyclic aromatic amines, derived from the pyrolysis of amino acids and proteins, are potent mutagens in the Ames Salmonella assay with rodent liver activation. Additionally, heterocyclic aromatic amines are multipotent carcinogens. We report evidence that these compounds are substrates for the hydroperoxidase activity of prostaglandin H synthase, as measured by alterations in UV/visible spectra, and are bioactivated to macromolecule-reactive species by this enzyme. Indirect electron paramagnetic resonance studies indicate that this activation may occur via a one-electron mechanism. 2-Amino-3-methylimidazo[4,5f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) are direct-acting mutagens in TA98. The mutagenicity of IQ and MeIQ, but not Trp-P-2, were enhanced by activation with ram seminal vesicle microsomes (a rich source of prostaglandin H synthase). Subsequent experiments utilized the newly constructed tester strain TA1538/1,8-DNP6 (pYG 121), which has enhanced arylamine N-acetyltransferase activity. In this strain IQ, MeIQ and 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole (Glu-P-1) were mutagenic with ram seminal vesicle microsome activation. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was a weak direct-acting mutagen, and was not activated by the ram seminal vesicles (RSV) system. The responses of IQ and MeIQ were markedly enhanced in TA1538/1.8-DNP6 (pYG 121), relative to TA98. These data are consistent with the involvement of prostaglandin H synthase-catalyzed activation in heterocyclic aromatic amine-induced extrahepatic neoplasia.
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