Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats

Chan, Wan; Luo, Hao; Zheng, Yufang; Cheng, Yuen Kit; Cai, Zongwei

doi:10.1124/dmd.106.013979

Cited by 56 publications

(81 citation statements)

References 27 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1) AAs refer to a mixture of structurally related nitrophenanthrene carboxylic acids whose major constituents include 8-methoxy-6-nitro-phenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (aristolochic acid I; AAI) and its 8-demethoxylated form (aristolochic acid II; AAII). 2,3) AAs are believed to be the causative agents in Balkan endemic nephropathy and Chinese herb nephropathy. 4) Botanic products known or suspected to contain AAs are not permitted to be sold worldwide, although they are still in used in traditional medicines in Asian countries.…”

mentioning

confidence: 99%

Uptake of Aristolochic Acid I into Caco-2 Cells by Monocarboxylic Acid Transporters

Kimura

Haraguchi

Ohta

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The uptake mechanism of aristolochic acid I (AAI) was investigated using Caco-2 cells cultured on dishes and permeable membranes. The uptake of AAI from the apical membrane of Caco-2 cells cultured on a dish was rapid, and a decrease in the pH of the incubation medium significantly increased uptake. Incubation at low temperature (4°C) and treatment with sodium azide (a metabolic inhibitor) or carbonylcyanide p-trifluoromethoxyphenylhydrazone (a protonophore) significantly inhibited the AAI uptake. Coincubation with L-lactic acid or benzoic acid, typical substrates for the proton-linked monocarboxylic acid transporters (MCTs), significantly decreased the AAI uptake, as did coincubation with α-cyano-4-hydroxycinnamate (an inhibitor of MCTs). Dixon plotting revealed the competitive inhibition of benzoic acid on the AAI uptake. To confirm the AAI uptake via MCTs, the apical-to-basolateral transport of AAI was investigated using the Caco-2 cells cultured on the permeable membranes. The transport of AAI at pH 6.0 was markedly higher than that at pH 7.4, and was significantly decreased by coincubation with benzoic acid. These results suggest that the uptake of AAI from the apical membrane of Caco-2 cells is mediated mainly by MCTs along with benzoic acid.

show abstract

mentioning

confidence: 99%

Uptake of Aristolochic Acid I into Caco-2 Cells by Monocarboxylic Acid Transporters

Kimura

Haraguchi

Ohta

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…The proposed activation and detoxification pathways of AAI are shown in Figure 3. AAI is activated by nitroreduction to N-hydroxyaristolactam I, a metabolite recently detected in the urine of AA-treated rats which confirms its formation during metabolism in vivo 33 . N-Hydroxyaristolactam I can form a cyclic N-acylnitrenium ion as the ultimate carcinogen binding to DNA.…”

Section: Metabolism Of Aristolochic Acid and Biotransformation Enzymesmentioning

confidence: 63%

“…3) as AAIa or its conjugates, the O-glucuronide, the O-acetate and the O-sulfate esters, are excreted in the urine 33,44 . AAIa is also reduced to N-hydroxyaristolactam Ia forming aristolactam Ia which together with its conjugates, the N -and O-glucuronides, is excreted 33,44 . Enzymatic reactions leading to aristolactam Ia and its metabolites seem to be solely a detoxification pathway because DNA adducts containing aristolactam Ia structure have, as yet, never been found.…”

Section: Metabolism Of Aristolochic Acid and Biotransformation Enzymesmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…After BNF treatment, both AAI and ALI were decreased, but AAIa was unchanged in either liver or kidney, compared to the vehicle-treated mice. The lack of increase in AAIa raises the possibility that AAIa might have undergone an extensively phase II conjugation and was readily eliminated from the body [31] . Furthermore, considering AAIa was much less cytotoxic and mutagenic than AAI [14,32] , we speculate that the formation of AAIa by CYP1A plays a role in detoxicification of AAI in vivo in contrast to its toxicity in vitro.…”

Section: Discussionmentioning

confidence: 99%

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

Xiao

Xue

et al. 2009

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim:The role of CYP1A in the protection of aristolochic acid (AA)I-induced nephrotoxicity has been suggested. In the present study we investigated the effects of β-naphthoflavone (BNF), a non-carcinogen CYP1A inducer, on AAI-induced kidney injury. Methods: Mice were pretreated with 80 mg/kg BNF by daily intraperitoneal injection (ip) for 3 days followed by a single ip of 10 mg/kg AAI. AAI and its major metabolites in blood, liver and kidney, the expression of CYP1A1 and CYP1A2 in microsomes of liver and kidney, as well as the nephrotoxicity were evaluated. Results: BNF pretreatment prevented AAI-induced renal damage by facilitating the disposal of AAI in liver. BNF pretreatment induced the expression of CYP1A1 in both liver and kidney; but the induction of CYP1A2 was only observed in liver. Conclusion: BNF prevents AAI-induced kidney toxicity primarily through CYP1A induction.

show abstract

Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats

Cited by 56 publications

References 27 publications

Uptake of Aristolochic Acid I into Caco-2 Cells by Monocarboxylic Acid Transporters

Uptake of Aristolochic Acid I into Caco-2 Cells by Monocarboxylic Acid Transporters

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

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

Contact Info

Product

Resources

About