Bioactivation of Nephrotoxic Haloalkenes by Glutathione Conjugation: Formation of Toxic and Mutagenic Intermediates by Cysteine Conjugate β-Lyase

Dekant, W.; Vamvakas, Spyridon; Anders, M.W.

doi:10.3109/03602538908994144

Cited by 153 publications

(50 citation statements)

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“…They are formed from many endogenous and exogenous compounds (Boyland and Chasseaud, 1969;Chasseaud, 1979;Dekant et al, 1989;Stevens and Jones, 1989;Ballatori, 1994;Wang and Ballatori, 1998). The exogenous compounds include drugs, natural toxins, and environmental pollutants, and the endogenous compounds include leukotrienes, prostaglandins, hepoxilin, nitric oxide, hydroxyalkenals, ascorbic acid, dihydroxyphenylalanine, dopamine, and maleic acid .…”

Section: Discussionmentioning

confidence: 99%

“…Mercapturic acids synthesized in other tissues enter the bloodstream and are eliminated by kidney and liver (Hinchman et al, 1998), although the relative contribution of these two organs, and possibly of other organs, remains to be established. Failure to remove mercapturic acids from either the blood or cells may result in toxicity and has been implicated as a causative factor in nephrotoxic disease (Dohn et al, 1985;Dekant et al, 1989;Stevens and Jones, 1989).…”

mentioning

confidence: 99%

“…Many potentially toxic metabolites of both endogenous and exogenous origin are eliminated from the body after their conversion to the corresponding mercapturic acids [i.e., Nacetyl-L-cysteine S-conjugates (Boyland and Chasseaud, 1969;Chasseaud, 1979;Dekant et al, 1989;Stevens and Jones, 1989;Hinchman et al, 1991Hinchman et al, , 1998Hinchman and Ballatori, 1994;Rebbeor et al, 1998;Wang and Ballatori, 1998)]. Mercapturic acid synthesis requires at least four enzymatic steps and three cell membrane transport events and is believed to require the interorgan shuttling of the metabolic intermediates (Stevens and Jones, 1989;Hinchman and Ballatori, 1994).…”

mentioning

confidence: 99%

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Mercapturic Acids (N-AcetylcysteineS-Conjugates) as Endogenous Substrates for the Renal Organic Anion Transporter-1

Pombrio

Giangreco

et al. 2001

Mol Pharmacol

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Mercapturic acids are N-acetyl-L-cysteine S-conjugates that are formed from a range of endogenous and exogenous chemicals. Although the kidney is a major site for elimination of mercapturic acids, the transport mechanisms involved have not been identified. The present study examined whether mercapturic acids are substrates for the renal basolateral organic anion transporter-1 (Oat1) from rat kidney. This carrier mediates uptake of organic anions from the bloodstream in exchange for intracellular ␣-ketoglutarate. Uptake of [ 3 H]p-aminohippuric acid (PAH) in Oat1-expressing Xenopus laevis oocytes was strongly inhibited by S-(2,4-dinitrophenyl)-N-acetyl-L-cysteine (DNP-NAC) and by all other mercapturic acids tested, including the endogenous mercapturic acid N-acetyl-leukotriene E 4 . Inhibition by the mercapturic acids was competitive, which is consistent with the hypothesis that these compounds are substrates for Oat1. This conclusion was supported by the direct demonstration of saturable [35 S]DNP-NAC uptake in Oat1-expressing oocytes. [35 S]DNP-NAC uptake was inhibited by PAH and other mercapturic acids and was stimulated in oocytes preloaded with glutarate. The apparent K m value for DNP-NAC uptake was only 2 M, indicating that this mercapturic acid is a high affinity substrate for Oat1. Together, these data indicate that clearance of endogenous mercapturic acids is an important function of the renal organic anion transporter.Many potentially toxic metabolites of both endogenous and exogenous origin are eliminated from the body after their conversion to the corresponding mercapturic acids [i.e., Nacetyl-L-cysteine S-conjugates

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Mercapturic Acids (N-AcetylcysteineS-Conjugates) as Endogenous Substrates for the Renal Organic Anion Transporter-1

Pombrio

Giangreco

et al. 2001

Mol Pharmacol

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“…In the bile of rats exposed to trichloroethene, tetrachloroethene, HCBD, TCTFP, or PFP, GSH S-conjugates identical to those formed in liver microsomes were present; in urine of exposed animals, halovinylmercapturic acids were definitively identified, demonstrating that GSH S-conjugate formation occurs in vivo (2).…”

Section: Introductionmentioning

confidence: 81%

“…1), as does metabolism of cysteine S-conjugates by P-lyase (2 to undergo Diels-Alder reactions with cyclopentadiene was used. When pentachlorobutadienyl 2-nitrophenyl disulfide was reduced in the presence of cyclopentadiene, a cyclopentadiene adduct indicative of a thioketene intermediate was identified (Fig.…”

Section: Genotoxicity Of S-conjugates In Bacteriamentioning

confidence: 99%

A Mechanism of Haloalkene-Induced Renal Carcinogenesis

Dekant¹,

Vamvakas²,

Koob³

et al. 1990

Environmental Health Perspectives

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Several halogenated alkenes are nephrotoxic; some others induce renal tubular adenocarcinomas in rodents after lifelong administration. A bioactivation mechanism accounting for the organ-selective tumor induction has been elucidated: conjugation of the parent compounds with glutathione (GSH), catalyzed by hepatic GSH S-transferases, results in the formation of haloalkyl and halovinyl glutathione S-conjugates. Formation of S-conjugates (identified by NMR and mass spectrometry) could be demonstrated with trichloroethene, tetrachloroethene, hexachlorobutadiene, perfluoropropene, trichlorotrifluoropropene, and dichloroacetylene in incubations with rat liver microsomes and in the isolated perfused rat liver. The GSH conjugates formed are eliminated from the rat liver with the bile and may be translocated to the kidney, intact or after metabolism to the corresponding cysteine S-conjugates that are metabolized in the kidney by renal tubular cysteine conjugate 3-lyase (P-lyase) to reactive intermediates, most likely thioacylchlorides and thioketenes. Interaction of these potent electrophiles with DNA [demonstrated for intermediates formed from S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine] causes mutagenicity in bacteria, genotoxicity in cultured renal cells, and cytotoxicity in kidney cells. As an alternative to 3-lyase-catalyzed cleavage, the cysteine S-conjugates may be acetylated to the corresponding mercapturic acids, which have been identified in urine. The ability of the kidney to concentrate GSH and cysteine S-conjugates and the intensive metabolism of GSH S-conjugates to cysteine S-conjugates in this organ are evidently responsible for the organotropic carcinogenicity.

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Role of SAM-dependent thiol methylation in the renal toxicity of several solvents in mice

et al. 1999

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Bioactivation of Nephrotoxic Haloalkenes by Glutathione Conjugation: Formation of Toxic and Mutagenic Intermediates by Cysteine Conjugate β-Lyase

Cited by 153 publications

References 133 publications

Mercapturic Acids (N-AcetylcysteineS-Conjugates) as Endogenous Substrates for the Renal Organic Anion Transporter-1

Mercapturic Acids (N-AcetylcysteineS-Conjugates) as Endogenous Substrates for the Renal Organic Anion Transporter-1

A Mechanism of Haloalkene-Induced Renal Carcinogenesis

Role of SAM-dependent thiol methylation in the renal toxicity of several solvents in mice

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