Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury

Xue, Xiang; Xiao, Ying; Zhu, Hongli L.; Wang, Hui; Liu, Yongzhen; Xie, Tongxin; Ren, Jin

doi:10.1093/ndt/gfn262

Cited by 34 publications

(27 citation statements)

References 25 publications

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“…Most importantly, in these studies AA induced either acute kidney failure or just mild changes in kidney fibrosis [25,27,28,29]. Most studies failed to show convincing images of kidney fibrosis [30,31,32]. Therefore, in this study, we aimed to develop a standardised protocol of kidney fibrosis in C57BL/6 mice using pure AAI, with extensive characterisation of tubulointerstitial fibrosis to demonstrate the relevance of the pathology to that in man.…”

Section: Introductionmentioning

confidence: 99%

Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

Huang¹,

Scarpellini²,

Funck³

et al. 2013

Nephron Extra

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Background: Genetically modified mice are used to investigate disease and assess potential interventions. However, research into kidney fibrosis is hampered by a lack of models of chronic kidney disease (CKD) in mice. Recently, aristolochic acid nephropathy (AAN), characterised by severe tubulointerstitial fibrosis, has been identified as a cause of end stage kidney disease and proposed as a model of CKD. Published studies have used various dosing regimens, species and strains, with variable outcomes. Therefore, we aimed to develop a standardised protocol to develop tubulointerstitial fibrosis using pure aristolochic acid I (AAI) in C57BL/6 mice. Methods: AAI dose optimisation was performed by intraperitoneal injection of AAI at varying dose, frequency and duration. Kidney function was assessed by serum creatinine. Fibrosis was quantified by hydroxyproline levels and Masson’s Trichrome staining. Specific collagens were measured by immunofluorescent staining. Results: Single doses of AAI of >10 mg/kg caused acute kidney failure and death. Lower doses of 2.5 mg/kg needed to be administrated more than weekly to cause significant fibrosis. 3 mg/kg once every 3 days for 6 weeks followed by a disease development time of 6 weeks after AAI led to reduced kidney weight and function. Substantial tubulointerstitial fibrosis occurred, with males more severely affected. Increased deposition of collagen I, III and IV contributed to fibrosis, with collagen III and IV higher in males. Conclusions: AAN can be induced in C57BL/6 mice. The regimen of 3 mg/kg every 3 days for 6 weeks followed by 6 weeks of disease development time gives substantial tubulointerstitial fibrosis with lesions similar to those in humans.

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Section: Introductionmentioning

confidence: 99%

Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

Huang¹,

Scarpellini²,

Funck³

et al. 2013

Nephron Extra

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“…In-vitro experiments using hepatic mouse microsomes show that CYP1A enzymes generate AAIa 47 . but the mouse model used to evaluate the role of CYP1A in the formation of AAIa in vivo by inducing CYP1A via 3-methycholanthrene (MC), produced ambiguous results 47,52 , MC induces other enzymes beside CYP1A. Although treatment of mice with MC leads to decrease in AAI concentrations in the liver and kidney, no increase in AAIa concentrations was found in the liver, only in the kidney of mice treated with the higher dose of AAI (20 mg/kg body weight).…”

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

confidence: 99%

“…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. To test this assumption and to complement earlier studies 25,45,47,52,54 , we are currently investigating the formation of AAI-DNA adducts in HRN and CYP1A gene knock-out mouse models.…”

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

confidence: 99%

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 Med Fac Univ Palacky Olomouc Czech Repub

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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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“…The pharmacokinetics of AAI in rodents Chen et al, 2008;Xue et al, 2008;Liu et al, 2009;Yue et al, 2009), and a few in herbivore, such as rabbits, have been reported (Chen et al, 2007). Chronic renal injuries, such as tubulointerstitial fibrosis and tumors, are induced by AAI in rodent.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of aristolochic acid I after oral administration of Radix Aristolochiae or Guanxinsuhe preparation in canines

Yang

Zheng

et al. 2011

Journal of Ethnopharmacology

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Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury

Abstract: These results demonstrated that the induction of hepatic P450 1A1/2 protected against AAI-induced kidney injury through faster in vivo clearance of AAI and suggested an important role for hepatic P450s in the detoxification of AAI-induced renal injury.

Cited by 34 publications

References 25 publications

Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

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

Kinetics of aristolochic acid I after oral administration of Radix Aristolochiae or Guanxinsuhe preparation in canines

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