Aristolochic acid (AA), a plant nephrotoxin and carcinogen, causes aristolochic acid nephropathy (AAN) and its associated
urothelial malignancy, and is hypothesized to be responsible for Balkan endemic nephropathy (BEN). The major component of AA, aristolochic
acid I (AAI), is the predominant compound responsible for these diseases. The reductive activation of AAI leads to the formation
of covalent DNA adducts. The most abundant DNA adduct, 7-(deoxyadenosin-N6-yl)aristolactam I, causes characteristic AT→TA transversions
found in the TP53 tumor suppressor gene in tumors from AAN and BEN patients. Understanding which human enzymes are involved
in AAI activation to species forming DNA adducts and/or detoxication to the AAI O-demethylated metabolite, aristolochic acid Ia
(AAIa), is important in the assessment of the susceptibility to this carcinogen. This review summarizes the latest data on identifying human
and rodent enzymes participating in AAI metabolism. NAD(P)H:quinone oxidoreductase (NQO1) is the most efficient cytosolic nitroreductase
activating AAI in vitro and in vivo. In human hepatic microsomes, AAI is activated by cytochrome P450 1A2 (CYP1A2)
and, to a lesser extent, by CYP1A1; NADPH:CYP oxidoreductase also plays a minor role. Human and rodent CYP1A1 and 1A2 are also
the principal enzymes involved in oxidative detoxication of AAI to AAIa in vitro and in vivo. The orientation of AAI in the active sites of
human CYP1A1/2 and NQO1 was predicted from molecular modeling and is consistent with the efficient reduction of AAI by them observed
experimentally. Molecular modeling also shows why CYP1A2 plays an important role in the oxidation of AAI to AAIa.
Keywords: Aristolochic acid, aristolochic acid nephropathy, Balkan endemic nephropathy, metabolic activation and detoxication; biotransformation
enzymes; NAD(P)H:quinone oxidoreductase, cytochromes P450 1A1 and 1A2.
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