Examination of the structure-toxicity relationships of l-cysteine-S-conjugates of halogenated alkenes and their corresponding mercapturic acids in rat renal tissue slices

Stijntjes, G.J.; Commandeur, Jan N. M.; Koppele, J.M. te; McGuinness, S.; Gandolfi, A. Jay; Vermeulen, Nico

doi:10.1016/0300-483x(93)90206-8

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…(Aminooxy)acetic acid, an inhibitor of /3-lyase (41), blocked the cytotoxicity of the S-conjugates, confirming a role for the /3-lyase in the bioactivation of the compounds. Previous studies demonstrated that DBDFC, CTFC, and TFC are cytotoxic in a range of in vitro test systems, including freshly isolated rat renal proximal tubular cells, primary cultures of rat renal proximal tubular cells, and rat renal tissue slices (31,(44)(45)(46). BCDFC has previously been shown to be cytotoxic in LLC-PK1 cells (28).…”

Section: Discussionmentioning

confidence: 99%

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Finkelstein

Vamvakas²,

Bittner³

et al. 1994

Chem. Res. Toxicol.

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Glutathione and cysteine S-conjugates of several haloalkenes are nephrotoxic and cytotoxic. Chloroalkene-derived S-(1-chloroalkenyl)-L-cysteine conjugates, but not fluoroalkene-derived S-(2,2-dihalo-1,1-difluorethyl)-L-cysteine conjugates, are mutagenic in the Ames test, although both types of S-conjugates are cytotoxic and nephrotoxic. Recent studies showed that bromine-containing S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are mutagenic in the Ames test, thus challenging the generalization that S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are not mutagenic. Hence a series of bromine-containing and bromine-lacking S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates was prepared, and their mutagenicity was assessed in the Ames test with Salmonella typhimurium TA2638 as the test strain. In addition, several indices of cytotoxicity, including cytotoxicity in LLC-PK1 cells, induction of Ca2+ release from pig kidney mitochondria, and DNA double-strand breaks in LLC-PK1 cells, were measured. The bromine-containing S-conjugates S-(2-bromo-2-chloro-1,1-difluoroethyl)-L- cysteine (BCD-FC), S-(2-bromo-1,1,2-trifluoroethyl)-L-cysteine (BTFC), and S-(2,2-dibromo-1,1-difluoroethyl)-L-cysteine (DBDFC) were mutagenic in the Ames test, whereas S-(2-chloro-1,1,2-trifluorethyl)-L-cysteine (CTFC), S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine (DCDFC), and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFC), which lack bromine, were not. BCDFC, BTFC, CTFC, DBDFC, and TFC were cytotoxic in LLC-PK1 cells, and their cytotoxicity was blocked by the cysteine conjugate beta-lyase inhibitor (aminooxy)acetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Finkelstein

Vamvakas²,

Bittner³

et al. 1994

Chem. Res. Toxicol.

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“…Interestingly, minor alleles of SNPs present in the promoter region of the NAT8 gene have been shown to confer a protective effect towards both elevated blood pressure and the risk of kidney failure (30). In view of the role of NAT8 as CCNAT, this protective effect may result from a higher ability to acetylate cysteine conjugates, which in the nonacetylated form are easily converted to nephrotoxic products (14,30,35,36). It would therefore be of interest to investigate if these minor alleles drive a higher expression of NAT8.…”

Section: Discussionmentioning

confidence: 99%

Molecular Identification of NAT8 as the Enzyme That Acetylates Cysteine S-Conjugates to Mercapturic Acids

Veiga‐da‐Cunha

Tyteca²,

Stroobant

et al. 2010

Journal of Biological Chemistry

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Our goal was to identify the reaction catalyzed by NAT8 (N-acetyltransferase 8), a putative N-acetyltransferase homologous to the enzyme (NAT8L) that produces N-acetylaspartate in brain. The almost exclusive expression of NAT8 in kidney and liver and its predicted association with the endoplasmic reticulum suggested that it was cysteinyl-S-conjugate N-acetyltransferase, the microsomal enzyme that catalyzes the last step of mercapturic acid formation. In agreement, HEK293T extracts of cells overexpressing NAT8 catalyzed the N-acetylation of S-benzyl-L-cysteine and leukotriene E 4 , two cysteine conjugates, but were inactive on other physiological amines or amino acids. Confocal microscopy indicated that NAT8 was associated with the endoplasmic reticulum. Neither of the two frequent single nucleotide polymorphisms found in NAT8, E104K nor F143S, changed the enzymatic activity or the expression of the protein by >2-fold, whereas a mutation (R149K) replacing an extremely conserved arginine suppressed the activity. Sequencing of genomic DNA and EST clones corresponding to the NAT8B gene, which resulted from duplication of the NAT8 gene in the primate lineage, disclosed the systematic presence of a premature stop codon at codon 16. Furthermore, truncated NAT8B and NAT8 proteins starting from the following methionine (Met-25) showed no cysteinyl-S-conjugate N-acetyltransferase activity when transfected in HEK293T cells. Taken together, these findings indicate that NAT8 is involved in mercapturic acid formation and confirm that NAT8B is an inactive gene in humans. NAT8 homologues are found in all vertebrate genomes, where they are often encoded by multiple, tandemly repeated genes as many other genes encoding xenobiotic metabolism enzymes. NAT8L (N-acetyltransferase 8-like) was recently identified as aspartate N-acetyltransferase, the enzyme that makes N-acetylaspartate, the second most abundant metabolite in mammalian brain (1). Aspartate N-acetyltransferase is a membrane-bound enzyme, which is inactivated by treatment with detergents and has therefore resisted various purification attempts. The approach used to determine the molecular identity of aspartate N-acetyltransferase was based on a database search for a putative mammalian protein that would have the characteristics expected for aspartate N-acetyltransferase, i.e. similarity to known N-acetyltransferases, predicted membrane association, and predominant brain expression. This search led to the selection of two candidates, one of which (NAT8L) proved experimentally to be aspartate N-acetyltransferase.The identification of the reaction catalyzed by NAT8L raises the question of the function of the related protein NAT8, a protein with 227 residues sharing about 30% sequence identity with NAT8L. This high similarity suggests that NAT8 also acetylates an amino acid. Furthermore, NAT8 and NAT8L share a similar hydrophobic domain that most likely anchors them to membranes, and NAT8 is predicted to be associated with the endoplasmic reticulum (ER), 3 as recently demonst...

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“…The bioactivation mechanism of DCDFE via primary GSH conjugation has been shown (Commandeur et al, 1987), as well as the nephrotoxicity of N-acetyl-S-(1,1-dichloro-2,2-difluoroethylene)cysteine (DCDFE-NAC) (Commandeur et al, 1987(Commandeur et al, , 1988Stijntjes et al, 1993). In addition, two urinary metabolites were identified, namely DCDFE-NAC (more abundant) and traces of chlorodifluoroacetic acid, which were only detected at the highest dose of DCDFE (Commandeur et al, 1987).…”

Section: Discussionmentioning

confidence: 96%

“…The bioactivation mechanism of CTFE via primary GSH conjugation has been shown (Dohn et al, 1985b), as well as the nephrotoxicity of S-(2-chloro-1,1,2-trifluroethyl)glutathione and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (Dohn et al, 1985b) and of N-acetyl-S(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (Commandeur et al, 1988;Boogaard et al, 1989;Stijntjes et al, 1993). The bioactivation mechanism of DCDFE via primary GSH conjugation has been shown (Commandeur et al, 1987), as well as the nephrotoxicity of N-acetyl-S-(1,1-dichloro-2,2-difluoroethylene)cysteine (DCDFE-NAC) (Commandeur et al, 1987(Commandeur et al, , 1988Stijntjes et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effect of β‐naphthoflavone and phenobarbital on the nephrotoxicity of chlorotrifluoroethylene and 1,1‐dichloro‐2,2‐difluoroethylene in the rat

Morel

Ban

Bonnet

et al. 2005

J of Applied Toxicology

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The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1/2 were induced by beta-naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications. Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of gamma-glutamyltranspeptidase (gamma GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl-beta-D-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and beta2-microglobulin (beta2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure. Beta-naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism.

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Examination of the structure-toxicity relationships of l-cysteine-S-conjugates of halogenated alkenes and their corresponding mercapturic acids in rat renal tissue slices

Cited by 14 publications

References 28 publications

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Molecular Identification of NAT8 as the Enzyme That Acetylates Cysteine S-Conjugates to Mercapturic Acids

Effect of β‐naphthoflavone and phenobarbital on the nephrotoxicity of chlorotrifluoroethylene and 1,1‐dichloro‐2,2‐difluoroethylene in the rat

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