A role of biotransformation enzymes in the Development of renal injury and urothelial cancer caused by aristolochic acid: Urgent questions difficult answers
Abstract
The most important human enzymes activating aristolochic acid I (AAI) by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 (CYP) 1A2 and renal microsomal NADPH:CYP reductase, besides cyclooxygenase, which is highly expressed in urothelial tissue. Despite extensive research, contribution of most of these enzymes to the development of AAN and BEN diseases is still unknown.
Hepatic CYP enzymes were found to detoxicate AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of a 1A subfamily seem to play the most important role in this process in mouse liver.
Likewise, among human CYP enzymes, CYP1A1 and 1A2 were found to be the most efficient enzymes participating in AAI oxidation to AAIa in vitro.