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Cytochrome P450 1A2 is responsible for detoxifying aristolochic acid in the mouse

Rosenquist, Thomas and Einolf, Heidi and Dickman, Kathleen and Wang, Lai and Smith, Amanda and Grollman, Arthur (2010) Cytochrome P450 1A2 is responsible for detoxifying aristolochic acid in the mouse. Drug Metabolism and Disposition, 38 (5). pp. 761-768. ISSN 0090-9556

Abstract

Aristolochic acids (AA) are plant-derived nephrotoxins and carcinogens responsible for chronic renal failure and associated urothelial cell cancers in several clinical syndromes known collectively as aristolochic acid nephropathy (AAN). The renal histopathology of AA-treated mice is strikingly similar to that of humans, and AA is a potent carcinogen in mice with a somewhat different tissue spectrum than in humans. The toxic dose of AA in mice is much higher than in humans, this difference in susceptability has been postulated to reflect differing rates of detoxification between the species. Of eighteen human CYP enzymes we surveyed, only two, CYP1A1 and CYP1A2 were effective in de-methylating AAI to the nontoxic derivative AAIa. Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We report here that mice lacking the Cyp1A2 gene display increased sensitivity to the nephrotoxic effects AAI. Cyp1a2 knockout mice also accumulate AAI-derived DNA adducts in the kidney at a higher rate than control mice. Differences in bioavailability or hepatic metabolism of AAI, expression of CYP1A2, or efficiency of the nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2275

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