Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity

Abstract

Cytochrome P450s metabolize the naturally occurring nephrotoxin aristolochic acid. Using liver-specific cytochrome P450 reductase-null mice we found that a low but lethal dose of aristolochic acid I was ineffective in wild-type mice. Induction of hepatic CYP1A by 3-methylcholanthrene pretreatment markedly increased the survival rate of wild type mice given higher doses and these mice were protected from aristolochic acid I-induced renal injury. Clearance of aristolochic acid I in null mice was slower compared to control and the 3-methylcholanthrene-pretreated wild type mice. The levels of aristolochic acid I in the kidney and liver were much higher in null mice but much lower in 3-methylcholanthrene-treated compared to control wild type mice. Hepatic microsomes from 3-methylcholanthrene-treated wild type mice had greater activity compared to untreated mice. Finally, aristolochic acid I was more cytotoxic than its major metabolite aristolactam I and this cytotoxicity was decreased in human renal tubular epithelial HK2 cells in the presence of a reconstituted hepatic microsome-cytosol (S9) system. These results indicate that hepatic P450s play an important role in metabolizing aristolochic acid I into less toxic metabolites and thus have a detoxification role in aristolochic acid I-induced kidney injury.

Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney

“…Because the physiological counteranions and gradients driving Oat2 transport have not been identified, it is unclear whether it functions in a secretory or reabsorptive mode. This transporter is also highly expressed in liver, the primary site of AA-I detoxification (Xiao et al, 2008). Hepatic Oat2 is localized to the basolateral (sinusoidal) membrane (Simonson et al, 1994), where it could conceivably mediate influx of AA-I or efflux of its metabolites, such as AA-Ia.…”

Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

“…, oxidative) conditions both CYP enzymes are able to O -demethylate AAI to a detoxification metabolite, 8-hydroxyaristolochic acid I (aristolochic acid Ia, AAIa; Figure 2). Under these (aerobic) conditions, AAI behaves as a classical substrate of human CYP1A1 and 1A2, where one oxygen atom is utilized for O -demethylation of AAI to form AAIa [46,47,62,86,87,89,91,92,93]. These experimental results strongly suggest that, besides CYP1A1 and 1A2 expression levels, the oxygen level in tissues affects the balance between AAI nitroreductive activation and oxidative detoxication by these CYPs in vivo [47,62,86,87,89].…”

Glutathione S-transferases T1 null genotype is associated with susceptibility to aristolochic acid nephropathy

“…Previous studies have demonstrated that most of the toxins are physiologically transported and metabolized in the organs (e.g., liver, kidneys) by some specific enzyme/protein, including P-glycoprotein [7], cytochrome P450 (CYP1A1) [8], NAD(P)H quinone oxidoreductase 1 (NQO1) [9] and glutathione S-transferase (GST) [10]. The expression and function of these enzymes/proteins may influence drug metabolism and transport [9,11,12].…”