Studies on the metabolism of aristolochic acids I and II

Abstract

1. After oral administration of aristolochic acid I (AAI) and aristolochic acid II (AAII) to rats, the following metabolites were isolated from the urine and their structures elucidated: aristolactam I, aristolactam Ia, aristolochic acid Ia, aristolic acid I and 3,4-methylenedioxy-8-hydroxy-1-phenanthrenecarboxylic acid (metabolites of AAI); or aristolactam Ia, aristolactam II and 3,4-methylenedioxy-1-phenanthrenecarboxylic acid (metabolites of AAII). A further metabolite of AAII having a lactam structure has not yet been isolated in pure form. 2. The metabolic pathways have been elucidated by administration of various metabolites. 3. The principal metabolite of AAI in rats was aristolactam Ia; 46% of the dose was excreted in the urine in form of this metabolite and 37% in the faeces. The other substances were minor metabolites. Those metabolites of AAII whose structures have been elucidated were minor metabolites; the largest proportion consisted of aristolactam II, which accounted for 4.6% in the urine and 8.9% in the faeces. 4. The mouse was the only animal which had the same metabolite patterns of AAI and AAII as those found in the rat. Not all the metabolites listed above were found in urine from guinea pigs, rabbits, dogs and man.

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

“…Finally, it has been noted that urine from AA-exposed humans contains metabolites of aristolactam but not those derived from AAIa (Krumbiegel et al, 1987). This implies that the nitroreduction pathway is more efficient than demethylation in metabolizing AAI in humans.…”

“…A:T3 T:A transversions, the most frequently observed mutation in the TP53 gene in urothelial tumors of patients with AAN and Balkan endemic nephropathy (Lord et al, 2004;Grollman et al, 2007), have been proposed to be a "fingerprint" mutation for aristolochic acid exposure . Furthermore, aristolactam metabolites are observed in the urine of various species treated with AA (Krumbiegel et al, 1987). Thus, this pathway is postulated to be universal in mammals.…”

“…AAIa and its metabolites have been observed in the urine and feces of rabbits, dogs, mice, and rats treated with AAI, but not in urine from humans exposed to AA (Krumbiegel et al, 1987).…”

Role of Environmental Toxins in Endemic (Balkan) Nephropathy

“…Aristolochic acid-I is metabolized via two major pathways. 43 Demethylation to aristolochic acid-Ia generates a non-nephrotoxic product that is subject to phase II biotransformation to form glucuronide or sulfate conjugates. Alternatively, reactions catalyzed by cellular nitroreductases (NR) generate reactive intermediates that form covalent adducts with DNA and protein.…”

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

“…It has been reported that in hepatic microsomes, AA is metabolized to aristolochic acid Ia (AAIa) under aerobic conditions in vitro [13,14] . An in vivo study suggests that aristolactams (AL) are the major metabolites in kidney [15] . Our previous studies demonstrated that AAI-induced nephrotoxicity was more severe when the liver-specific NADPH-cytochrome P450 reductase (CPR) was deficient [16] , and the induction of CYP1A significantly reduced AAI-induced kidney toxicity in wild-type mice [17] .…”