PT  - JOURNAL ARTICLE
AU  - Thomas A. Rosenquist
AU  - Heidi J. Einolf
AU  - Kathleen G. Dickman
AU  - Lai Wang
AU  - Amanda Smith
AU  - Arthur P. Grollman
TI  - Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse
AID  - 10.1124/dmd.110.032201
DP  - 2010 May 01
TA  - Drug Metabolism and Disposition
PG  - 761--768
VI  - 38
IP  - 5
4099  - http://dmd.aspetjournals.org/content/38/5/761.short
4100  - http://dmd.aspetjournals.org/content/38/5/761.full
SO  - Drug Metab Dispos2010 May 01; 38
AB  - Aristolochic acids (AAs) 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). Mice provide a useful model for study of AAN because the renal histopathology of AA-treated mice is strikingly similar to that of humans. AA is also a potent carcinogen in mice with a tissue spectrum somewhat different from that in humans. The toxic dose of AA in mice is higher than that in humans; this difference in susceptibility has been postulated to reflect differing rates of detoxication between the species. Recent studies in mice have shown that the hepatic cytochrome P450 system detoxicates AA, and inducers of the arylhydrocarbon response protect mice from the nephrotoxic effects of AA. The purpose of this study was to determine the role of specific cytochrome P450 (P450) enzymes in AA metabolism in vivo. Of 18 human P450 enzymes we surveyed only two, CYP1A1 and CYP1A2, which were effective in demethylating 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) to the nontoxic derivative 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa). Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We also report here that CYP1A2-deficient mice display increased sensitivity to the nephrotoxic effects of AAI. Furthermore, Cyp1a2 knockout mice 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 a competing nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics