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.
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.
Commandeur
J N
JN
Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
Stijntjes
G J
GJ
Wijngaard
J
J
Vermeulen
N P
NP
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
D017402:Chlorofluorocarbons; D005030:Ethylenes; D006845:Hydrocarbons, Fluorinated; D006846:Hydrocarbons, Halogenated; C016304:chlorotrifluoroethylene; D003903:Deuterium; D001191:Arylamine N-Acetyltransferase; D000581:Amidohydrolases; D003545:Cysteine; D000111:Acetylcysteine