The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen

Stiborová, Marie; Sopko, B.; Hodek, Petr; Frei, Eva; Schmeiser, Heinz H.; Hudeček, Jiřı́

doi:10.1016/j.canlet.2005.06.038

Cited by 40 publications

(43 citation statements)

References 49 publications

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“…These include the microsomal enzymes NADPH: cytochrome P450 reductase (Stiborová et al, 2001c(Stiborová et al, , 2005a, prostaglandin H synthase (Stiborová et al, 2001a(Stiborová et al, , 2005a, and CYP1A1/2 under anaerobic conditions (Schmeiser et al, 1986;Stiborová et al, 2001bStiborová et al, , 2005b. Cytoplasmic enzymes implicated in AA activation include NAD(P)H:quinone oxidoreductase (Stiborová et al, 2002(Stiborová et al, , 2003(Stiborová et al, , 2005a and sulfotransferase A1 (Meinl et al, 2006).…”

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confidence: 99%

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

Rosenquist¹,

Einolf²,

Dickman³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Aristolochic acids (AAs) are plant-derived nephrotoxins and carcinogens responsible for chronic renal failure and associated urothelial cell cancers in several clinical syndromes known collectively as aristolochic acid nephropathy (AAN). Mice provide a useful model for study of AAN because the renal histopathology of AA-treated mice is strikingly similar to that of humans. AA is also a potent carcinogen in mice with a tissue spectrum somewhat different from that in humans. The toxic dose of AA in mice is higher than that in humans; this difference in susceptibility has been postulated to reflect differing rates of detoxication between the species. Recent studies in mice have shown that the hepatic cytochrome P450 system detoxicates AA, and inducers of the arylhydrocarbon response protect mice from the nephrotoxic effects of AA. The purpose of this study was to determine the role of specific cytochrome P450 (P450) enzymes in AA metabolism in vivo. Of 18 human P450 enzymes we surveyed only two, CYP1A1 and CYP1A2, which were effective in demethylating 8-methoxy-6-nitro-phenanthro- (3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) to the nontoxic derivative 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa). Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We also report here that CYP1A2-deficient mice display increased sensitivity to the nephrotoxic effects of AAI. Furthermore, Cyp1a2 knockout mice accumulate AAI-derived DNA adducts in the kidney at a higher rate than control mice. Differences in bioavailability or hepatic metabolism of AAI, expression of CYP1A2, or efficiency of a competing nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI.

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confidence: 99%

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

Rosenquist¹,

Einolf²,

Dickman³

et al. 2010

Drug Metab Dispos

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“…The literature on the role of CYP1A in AAI detoxication 45,47 combined with the reports found for CYP1A -and NQO1-mediated AAI activation 25,34,35,37,38 , strongly support the hypothesis 25 that a key factor determining the carcinogenic and nephrotoxic effects of AAI, is the balance of reductase activity such as NQO1, catalyzing the AAI-DNA adduct formation and enzymes such as CYPs which can both activate and detoxify AAI. Taking into account all the currently known data, we propose that the pathways of AAI metabolism are determined by: the binding affinity of AAI to CYP1A or NQO1 enzymes and their enzymatic turnover, as well as the balance between the efficiency of CYP1A in oxidizing and reducing AAI.…”

Section: The Role Of Biotransformation Enzymes In the Development Of mentioning

confidence: 82%

“…Other CYPs such as CYP1B1, 2C8, 3A4 as well as CYP2B6 with cytochrome b 5 , can also oxidize AAI but with efficiencies more than one order of magnitude lower than CYP1A 45 . However, we found that under the anaerobic conditions, human CYP1A enzymes also reductively activate AAI to species forming DNA adducts 37,38 . Therefore, the oxygen concentration of tissues may affect the relative extent of AAI activation by nitroreduction and its detoxication by O-demethylation.…”

Section: The Role Of Biotransformation Enzymes In the Development Of mentioning

confidence: 83%

“…This leads to dA-AAI, the most persistent adduct in initiating car- 25 . Several in-vitro studies report that the most important human and rat enzyme to activate AAI in vitro in hepatic or renal cytosolic subcellular fractions, is NAD(P)H:quinone oxidoreductase (NQO1) [34][35][36] followed by cytochrome P450 (CYP) 1A1/2 in hepatic microsomes 37,38 and NADPH:CYP reductase (POR) in renal microsomes 36,39 . In addition, prostaglandin H synthase (cyclooxygenase, COX) is able to bioactivate AAI 36,40 , which is highly expressed in urothelial tissue.…”

Section: Metabolism Of Aristolochic Acid and Biotransformation Enzymesmentioning

confidence: 99%

“…An increase in AAIa excretion due to its conjugation with glucuronide, caused by induction of UDP-glucuronosyltransferase with MC, could occur. However as CYP1A enzymes also activate AAI to species forming DNA adducts 25,[36][37][38] , the decrease in AAI in liver and kidney might also result from this reaction. Also, NQO1 which is also efficiently induced by MC, could contribute to decreased AAI levels in MC-treated mice.…”

Section: The Role Of Biotransformation Enzymes In the Development Of mentioning

confidence: 99%

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

Stiborová¹,

Frei²,

Arlt³

et al. 2009

BIOMED PAP

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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.

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Aristolochic Acid and Chinese Herb Nephropathy

Barceloux

2008

Medical Toxicology of Natural Substances

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Physical Description: This herb is a perennial climbing vine with a slender, gray -brown stem that contains brown villi. The oblong or ovate -shaped leaves are petioled and relatively large, 3 -11 cm ( ∼ 1 -4 in.) long and 2 -6 cm (0.8 -2.4 in.) wide. The tubular, purple fl ower is 2 -3 cm ( ∼ .8 -1.2 in.) long with yellow spots. The fl owers bloom in May and June. The capsules contain many seeds. Distribution and Ecology: The Aristolochiaceae family comprises seven genera of herbs and shrubs Chapter 47

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The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen

Cited by 40 publications

References 49 publications

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

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

Aristolochic Acid and Chinese Herb Nephropathy

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