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.

Department of Biochemistry Faculty of Science Charles University Prague Albertov 2030 128 40 Prague 2 Czech Republic

Citace poskytuje Crossref.org

Aristolochic acid-associated cancers: a public health risk in need of global action

Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer

Comparison of the oxidation of carcinogenic aristolochic acid I and II by microsomal cytochromes P450 in vitro: experimental and theoretical approaches

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

Balkan endemic nephropathy: an update on its aetiology

Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

Active Site Mutations as a Suitable Tool Contributing to Explain a Mechanism of Aristolochic Acid I Nitroreduction by Cytochromes P450 1A1, 1A2 and 1B1

A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches

Mechanisms of enzyme-catalyzed reduction of two carcinogenic nitro-aromatics, 3-nitrobenzanthrone and aristolochic acid I: Experimental and theoretical approaches