Metabolism of 1-chloro-2-methylpropene. Evidence for reactive chloroaldehyde intermediates.
Recent metabolism and disposition studies of 1-chloro-2-methylpropene (dimethylvinyl chloride) revealed cysteine and N-acetylcysteine conjugates of 3-chloro-2-methylpropenoic acid as the major metabolites. In the present studies we have investigated various steps in the metabolic pathway to determine which step was responsible for the observed trans (E)-stereochemistry of these metabolites. In vitro incubation studies of dimethylvinyl chloride with rat liver microsomes indicated cytochrome P-450-catalyzed aliphatic hydroxylation to be only stereoselective. Both (E)- and (Z)-3-chloro-2-methylpropenols formed in an identical ratio of 2:1 in incubations with microsomes from untreated male and female rats and phenobarbital-treated male rats. No alcohol formation was observed in incubations using microsomes from beta-naphthoflavone-treated male rats. Investigation of the subsequent conjugation reactions of sulfur nucleophiles with haloenoic carbonyl compounds showed that both (E)- and (Z)-3-chloro-2-methylpropenals reacted rapidly with N-acetylcysteine, the E-adduct being the sole product in either case. In contrast, the Michael reaction of the corresponding acids with N-acetylcysteine was very sluggish. Also, whereas the E-acid yielded exclusively the corresponding E-adduct, the Z-isomer afforded both Z- and E-conjugates in the ratio of 3:4. Glutathione S-transferases had poor activity towards conjugation of glutathione with these acids. Formation of only an E-glutathione conjugate could be observed from either the E- or Z-acid in these enzymatic reactions. Direct Michael reaction of glutathione with (E)-3-bromo-2-methylpropenoic acid, used in chemical synthesis of the conjugates, yielded both the E- and Z-adducts in the ratio of 95:5.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D014752:Vinyl Chloride / Q000031:analogs & derivatives / Q000378:metabolism*; D014753:Vinyl Compounds / Q000378:metabolism*
D002273:Carcinogens; D014753:Vinyl Compounds; C051950:1-chloro-2-methylpropene; D005982:Glutathione Transferase; D005978:Glutathione; D014752:Vinyl Chloride