title: Metabolism of L-cysteine S-conjugates and N-(trideuteroacetyl)-L-cysteine S-conjugates of four fluoroethylenes in the rat. Role of balance of deacetylation and acetylation in relation to the nephrotoxicity of mercapturic acids.
abstract: The relationship between the relative nephrotoxicity of the mercapturic acids (NAc) of the fluorinated ethylenes tetrafluoroethylene (TFE), chlorotrifluoroethylene (CTFE), 1,1-dichloro-2,2-difluoroethylene (DCDFE) and 1,1-dibromo-2,2-difluoroethylene (DBDFE), and the biotransformation by activating (N-deacetylase and beta-lyase) and inactivating (N-acetyltransferase) enzymes was studied in the rat. After intraperitoneal (i.p.) administration of 50 mumol/kg of N-(trideuteroacetyl)-labeled mercapturic acids of DCDFE and DBDFE to rats, significant amounts of the dose were excreted unchanged: with DCDFE-NAc, 17% of the dose, and DBDFE-NAc, 31% of the dose. In contrast, the corresponding deuterium-labeled mercapturic acids of TFE and CTFE were excreted unchanged at less than 1% of the dose. With DCDFE-NAc and DBDFE-NAc, also high amounts of unlabeled mercapturic acids were excreted, respectively 48% and 28% of the dose, indicating extensive N-deacetylation followed by reacetylation in vivo. Only small amounts (less than 2%) of unlabeled mercapturic acids were excreted with TFE-NAc and CTFE-NAc. After administration of the cysteine S-conjugates DCDFE-Cys and DBDFE-Cys to rats, high amounts of the corresponding mercapturic acids were detected in urine, respectively 57% and 45% of the dose. After administration of TFE-Cys and CTFE-Cys, however, only small amounts were excreted as the corresponding mercapturic acid, approximately 4% of the dose. The strongly different amounts of mercapturic acids in urine may be attributed to the strong differences in N-deacetylation activities which were found in rat renal fractions. The threshold dose of the mercapturic acids to cause nephrotoxicity in male Wistar rats increased in the order: CTFE-NAc (25 mumol/kg) less than TFE-NAc (50 mumol/kg) less than DCDFE-NAc (75 mumol/kg) less than DBDFE-NAc (100 mumol/kg). A higher ratio of N-deacetylation and N-acetylation activities, resulting in a higher availability of cysteine S-conjugate, in addition to a higher specific activity of cysteine S-conjugate beta-lyase, probably explains the higher nephrotoxicity of TFE-NAc and CTFE-NAc when compared to DCDFE-NAc and DBDFE-NAc. The much lower activities of N-deacetylation and beta-lyase which are observed in hepatic fractions may explain the lack of hepatotoxicity of the mercapturic acids studied.
authors.affiliation: Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
authors.forename: J N
authors.initials: JN
authors.lastname: Commandeur
authors.forename: G J
authors.initials: GJ
authors.lastname: Stijntjes
authors.forename: J
authors.initials: J
authors.lastname: Wijngaard
authors.forename: N P
authors.initials: NP
authors.lastname: Vermeulen
mesh_terms: D000107:Acetylation; D000111:Acetylcysteine / Q000493:pharmacokinetics* / Q000652:urine; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D017402:Chlorofluorocarbons; D003545:Cysteine / Q000493:pharmacokinetics / Q000652:urine; D003903:Deuterium; D005030:Ethylenes / Q000493:pharmacokinetics* / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000652:urine*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D017402:Chlorofluorocarbons; D005030:Ethylenes; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; C016304:chlorotrifluoroethylene; D003903:Deuterium; D001191:Arylamine N-Acetyltransferase; D000581:Amidohydrolases; D003545:Cysteine; D000111:Acetylcysteine