Inhibition of mouse embryonic, yolk sac, and limb-bud functions by the methyl isocyanate metabolite S-(N-methylcarbamoyl)glutathione.
We previously reported that S-(N-methylcarbamoyl)glutathione (SMG), a conjugate formed by the reversible reaction between methyl isocyanate and glutathione, inhibited the development of mouse embryos in culture. The present study was done to determine whether SMG produced embryotoxicity by inhibiting yolk sac functions. For this purpose we determined the effects of an embryotoxic concentration of SMG on mouse yolk sac uptake mechanisms and lysosomal proteolysis as well as on the incorporation of [3H]leucine in mouse embryonic and limb-bud proteins. After 5 h of culture, SMG inhibited the uptake of [14C]sucrose and 125I-labelled bovine serum albumin in isolated day 15 yolk sacs to 62 and 77% of control, respectively. Lysosomal proteolysis was not inhibited, as judged by the release of trichloroacetic acid soluble radioactivity into the culture media. Uptake and incorporation of [3H]leucine from free [3H]leucine or from [3H]leucine-labelled protein in SMG-treated day 9 embryos were inhibited, respectively, to 61 and 25% of the control uptake during a 16-h labelling period. SMG also inhibited the incorporation of free [3H]leucine into limb-bud proteins. SMG-induced inhibition of 125I-labelled bovine serum albumin uptake by yolk sacs was partially prevented by the thiol donors N-acetylcysteine and glutathione but not by acivicin (gamma-glutamyl transpeptidase inhibitor) and aminooxyacetic acid (cysteine conjugate beta-lyase inhibitor). These data suggest that SMG suppresses embryonic growth primarily by an inhibition of nutrient uptake by the yolk sac. We postulate that this inhibition is due to tissue carbamoylation by methyl isocyanate released from SMG.
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Department of Pharmacology and Therapeutics, McGill University, Montréal, PQ, Canada.
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D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D005121:Extremities / Q000196:embryology*; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D017953:Isocyanates / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D010873:Pinocytosis / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012711:Serum Albumin, Radio-Iodinated; D015017:Yolk Sac / Q000187:drug effects* / Q000378:metabolism
D000963:Antimetabolites; D001798:Blood Proteins; D017953:Isocyanates; D007555:Isoxazoles; D012711:Serum Albumin, Radio-Iodinated; D000625:Aminooxyacetic Acid; C053323:S-(N-methylcarbamoyl)glutathione; C008461:methyl isocyanate; D005978:Glutathione; D007930:Leucine; C006303:acivicin