Identification of N-acetyl(2,2-dichlorovinyl)- and N-acetyl(1,2-dichlorovinyl)-L-cysteine as two regioisomeric mercapturic acids of trichloroethylene in the rat.
The regioselectivity of glutathione conjugation to trichloroethylene (TRI) and the metabolism of its cysteine and N-acetyl-L-cysteine conjugates were investigated in the rat. Intraperitoneal (ip) administration of TRI to rats at a dose of 400 mg/kg resulted in excretion in urine of small amounts of the two distinct regioisomers N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-NAC) and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCV-NAC). The vicinal (vic) isomer was excreted in a 2 times higher amount (16 nmol) than the geminal (gem) isomer (8 nmol). Intraperitoneal administration of a 1:1 mixture (2.5 mumol/kg each) of the two regioisomers of S-(dichlorovinyl)-L-cysteine (DCVC) to the rat resulted in excretion of the corresponding mercapturic acids in urine, the main fractions being excreted within 8 h after administration. The gem-dichlorovinyl isomer appeared to be acetylated to a higher extend than the 1,2-dichlorovinyl isomer; 73% vs 50% of the dose administered. Intraperitoneal administration of a 1:1 mixture (12.5 mumol/kg each) of the two regioisomers of N-(trideuterioacetyl)-S-(dichlorovinyl)-L-cysteine (DCV-NAC-d3) resulted in excretion of both deuterium-labeled and unlabeled mercapturic acids in urine. The vic isomer was excreted unchanged at a significantly higher percentage, 34% of dose (i.e., still deuterium labeled), than the gem isomer, 17% of the dose. This suggests less efficient metabolism of the vic isomer when compared to the gem isomer. Both regioisomers of DCV-NAC-d3 were excreted in urine unlabeled at 40% of the dose, which indicates that for both isomers deacetylation, followed by reacetylation (resulting in unlabeled DCV-NAC), is an important metabolic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Commandeur
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JN
Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
Vermeulen
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D000107:Acetylation; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D002247:Carbon Isotopes; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D011522:Protons; D051381:Rats; D011919:Rats, Inbred Strains; D014241:Trichloroethylene / Q000378:metabolism*
D002247:Carbon Isotopes; D011522:Protons; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; C071767:N-acetyl-(2,2-dichlorovinyl)cysteine; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine; D000111:Acetylcysteine