Prostaglandin hydroperoxidase-dependent activation of heterocyclic aromatic amines

Carcinogenesis
T W PetryT E Eling

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-A...Continue Reading

Citations

Jan 1, 1991·Chemico-biological Interactions·B J SmithT E Eling
Jan 1, 1992·Pharmacology & Therapeutics·F P Guengerich
Mar 1, 1991·Mutation Research·H U Aeschbacher, R J Turesky
Jun 1, 2000·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·E WolzG H Degen
Jun 6, 2000·Mutation Research·T M de Kok, J M van Maanen
Dec 14, 2006·Prostaglandins & Other Lipid Mediators·Ying Yu, Colin D Funk
Jan 1, 1994·Environmental and Molecular Mutagenesis·R Rodriguez-Arnaiz, J H Aranda
Sep 17, 2021·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Takehiko Nohmi, Masahiko Watanabe

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