Study of the phase I and phase II metabolism of nephrotoxin aristolochic acid by liquid chromatography/tandem mass spectrometry

Chan, Wan; Cui, Liang; Xu, Guofeng; Cai, Zongwei

doi:10.1002/rcm.2513

Cited by 81 publications

(116 citation statements)

References 23 publications

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“…Metabolites, presumably derived from extrarenal and intrarenal reactions, predominate in urine, which contains little, if any, AA-I. Major urinary metabolites include AA-Ia, aristolactams I and Ia, phase II conjugates of AA-Ia and aristolactam Ia, along with small amounts of desnitro and descarboxy AA-I (Krumbiegel et al, 1987;Chan et al, 2006).…”

Section: Oats As Mediators Of Aristolochic Acid Nephropathy 593mentioning

confidence: 99%

Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney

Dickman

Sweet²,

Bonala³

et al. 2011

J Pharmacol Exp Ther

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Consumption of herbal medicines derived fromAristolochia plants is associated with a progressive tubulointerstitial disease known as aristolochic acid (AA) nephropathy. The nephrotoxin produced naturally by these plants is AA-I, a nitrophenanthrene carboxylic acid that selectively targets the proximal tubule. This nephron segment is prone to toxic injury because of its role in secretory elimination of drugs and other xenobiotics. Here, we characterize the handling of AA-I by membrane transporters involved in renal organic anion transport. Uptake assays in heterologous expression systems identified murine organic anion transporters (mOat1, mOat2, and mOat3) as capable of mediating transport of AA-I. Kinetic analyses showed that all three transporters have an affinity for AA-I in the submicromolar range and thus are likely to operate at toxicologically relevant concentrations in vivo. Structure-activity relationships revealed that the carboxyl group is critical for high-affinity interaction of AA-I with mOat1, mOat2, and mOat3, whereas the nitro group is required only by mOat1. Furthermore, the 8-methoxy group, although essential for toxicity, was not requisite for transport. Mouse renal cortical slices avidly accumulated AA-I, achieving slice-to-medium concentration ratios Ͼ10. Uptake by slices was sensitive to known mOat1 and mOat3 substrates and the organic anion transport inhibitor probenecid, which also blocked the production of DNA adducts formed with reactive intracellular metabolites of AA-I. Taken together, these findings indicate that OAT family members mediate high-affinity transport of AA-I and may be involved in the site-selective toxicity and renal elimination of this nephrotoxin.

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Section: Oats As Mediators Of Aristolochic Acid Nephropathy 593mentioning

confidence: 99%

Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney

Dickman

Sweet²,

Bonala³

et al. 2011

J Pharmacol Exp Ther

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“…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

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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.

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“…Previous studies have shown that the major metabolites of AAs in rats were produced from nitroreduction, O-demethylation, and denitration. O-Demethylation and hydroxylation were also observed in aristolactam I and aristolactam II, respectively, producing aristolactam Ia as the common end-stage reductive metabolite (Krumbiegel et al, 1987;Chan et al, 2006). The formation of hydroxylamine upon metabolic activation is believed to be the key step for the AA carcinogenicity.…”

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confidence: 99%

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

et al. 2007

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ABSTRACT:The metabolic activation of aristolochic acids (AAs) that have been demonstrated to be mutagenic and carcinogenic was investigated. In vitro metabolism study indicated that AAs were metabolized to N-hydroxyaristolactam, which could be either reduced to aristolactams or rearranged to 7-hydroxyaristolactams via the Bamberger rearrangement. In vivo metabolism study is important because the intermediates (aristolactam-nitriumion) of the nitroreduction process are thought to be responsible for the carcinogenicity of AAs. Liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (MS/MS) were applied to the analyses of a series of positional isomers of hydroxyaristolactams in rat urine samples after the in vivo study of AAs. Three hydroxylated metabolites of aristolactam II and two hydroxylated metabolites of aristolactam I were identified. The structures of the positional isomers were elucidated from the interpretation of MS/MS spectra and theoretical calculations. In addition, several new metabolites were detected in the rat urine by high-resolution mass spectrometry and MS/MS, including those from the decarboxylation of AAs and the conjugations of acetylation, glucuronidation, and sulfation of aristolochic acid Ia.

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Study of the phase I and phase II metabolism of nephrotoxin aristolochic acid by liquid chromatography/tandem mass spectrometry

Cited by 81 publications

References 23 publications

Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney

Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney

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

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

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