Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

Abstract

ABSTRACT: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.

Aristolochic Acid I Metabolism in the Isolated Perfused Rat Kidney

“…30 Consequently, AA-I demethylation, mediated by Cyp1A2 is a primary pathway of AA-I detoxication. 28,30 …”

“…As stated above, the most important human and rat enzymes activating and detoxicating AA-I in liver are NQO1, CYP1A1 and CYP1A2. 15,27,29,30 …”

Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

“…Gene-targeted mouse models confirm the role of hepatic cytochrome P-450 enzymes in detoxifying AA in vivo (69 -71). In the mouse, the primary CYP that metabolizes AAI is CYP1A2 (48), and human CYP1A2 is kinetically competent to metabolize AAI as well. Although a pilot genetic study found a potential link of the Cyp3A5*1 allele with BEN (6), CYP3A5 does not metabolize AA in vitro (48,53).…”

“…In the mouse, the primary CYP that metabolizes AAI is CYP1A2 (48), and human CYP1A2 is kinetically competent to metabolize AAI as well. Although a pilot genetic study found a potential link of the Cyp3A5*1 allele with BEN (6), CYP3A5 does not metabolize AA in vitro (48,53). Other studies have failed to establish a genetic link between known functional alleles in several CYPs, nitroreductases, or phase II genes and BEN (5,6,64).…”

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

“…In humans, CYP2C9 is reported to be the major AA-metabolizing enzyme, beside CYP1A1 and CYP1A2, which also have a robust AAI demethylating activity. 36 Acetyl-CoA-acyltransferase (Acaa1) was also reported to predict renal insult induced by different nephrotoxic compounds, including cadmium. 29 The fact that several drug-metabolizing enzymes, such as a-GST and p-GST, were also included into the urinary biomarker panel shows the important role of this class of enzymes in acute drug-induced tissue responses and in their potential to detect acute cellular changes.…”