The Role of Biotransformation Enzymes in the Development of Renal Injury and Urothelial Cancer Caused by Aristolochic Acid: Urgent Questions and Difficult Answers

Abstract

Background: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause another type of kidney fibrosis with malignant transformation of the urothelium, called Balkan Endemic Nephropathy (BEN). The compound predominantly responsible for the nephropathy and urothelial cancer of AA, is aristolochic acid I (AAI) which is a genotoxic mutagen after metabolic activation The activation pathway involves reduction of the nitro group to a cyclic N-acylnitrenium ion that can form covalent DNA adducts. These specific DNA adducts have been detected in experimental animals exposed to AAI, and in urothelial tissues from AAN patients. In rodent tumours induced by AAI, 7-(deoxyadenosin-N 6 -yl)aristolactam I was the most abundant DNA adduct formed and associated with activation of ras oncogenes through a characteristic transversion mutation. Such A:TT:A mutations have been identified in TP53 of urothelial tumour DNA of an AAN patient and in several patients suffering from BEN along with specific AA-DNA adducts. Understanding which enzymes are involved in AAI activation to species forming DNA adducts and/or detoxification to its O-demethylated metabolite aristolochic acid Ia (AAIa) is important in order to assess susceptibility to this carcinogen.Methods and Results: A literature search. Conclusions:The most important human enzymes activating 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 as well as cyclooxygenase which is highly expressed in urothelial tissue. However, the contribution of most of these enzymes to the development of AAN and BEN diseases is still unclear. Hepatic CYP enzymes were found to detoxify AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of the 1A subfamily seem to play a major 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. Nevertheless, which CYPs are the most important in this process in both animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AAI to species responsible for induction of urothelial cancer in humans remains still to be resolved.

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

“…Unfortunately, cases of severe renal injury were recently found in patients who used herbs containing AA components. Strangely, not all individuals develop the disease when exposed to AA, according to clinical observations [21], suggesting that individual differences in susceptibility to AAN may be partly linked to genetics [14]. In the present study, the common polymorphisms of CYP1A1 A4889G, NQO1 C609T, MDR1 C3435T and MDR1 G2677T/A, as well as GSTM1 null and GSTT1 null, were scanned in 91 cases with a clear, substantial history of using herb preparations containing AA.…”

“…Chinese herbs containing AA have proven to be potentially nephrotoxic, but not all individuals that are exposed to AA are susceptible to develop AAN [14]. Therefore, it is rational to postulate that genetic variation in individuals, including genes that control drug transport and metabolism, may play an important role in determining susceptibility to AAN.…”

An Exploratory Evaluation of the Utility of Transcriptional and Urinary Kidney Injury Biomarkers for the Prediction of Aristolochic Acid–Induced Renal Injury in Male Rats

“…Shown is the toxification process of AA to the reactive metabolite, a cyclic nitrenium ion, by the NAD(P)H:quinone oxidoreductase (Nqo1) and the resulting DNA adducts. [39][40][41][42] A reactive metabolite oxidative stress-driven response leading to Nrf2-mediated signaling and the induction of Nrf2-regulated genes such as Nqo1, Ephx1, GSTs, UGTs, and Mgmt.…”

“…16,18 The mechanism of AA nephrotoxicity and carcinogenicity is not fully understood but is thought to involve metabolic activation to a cyclic N-acylnitrenium ion that forms covalent DNA adducts. 3,19,42,50 Subchronic treatment of rats with 10 mg/kg body weight (BW) AA given as a mixture of AAI (77%) and AAII (21%) was shown to cause tumors in the forestomach, kidney, and the urinary bladder. 27 In a 28-day study, AA given at doses !5 mg/kg BW resulted in clear toxicity, whereas mild renal changes were seen at 1 mg/kg BW.…”

A fluorescence-based analysis of aristolochic acid-derived DNA adducts

“…These specific DNA adducts have been detected in renal and urothelial tissue of exposed experimental animals and patients [3]. …”