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Chloropicrin dechlorination in relation to toxic action
Author(s) -
Sparks Susan E.,
Quistad Gary B.,
Li Weiwei,
Casida John E.
Publication year - 2000
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/(sici)1099-0461(2000)14:1<26::aid-jbt4>3.0.co;2-t
Subject(s) - chemistry , toxicity , cytotoxicity , glutathione , biochemistry , lactate dehydrogenase , succinate dehydrogenase , dehydrogenase , metabolism , mechanism of action , enzyme , pharmacology , in vitro , biology , organic chemistry
Chloropicrin (CCl 3 NO 2 ) is a widely used soil fumigant with an unknown mechanism of acute toxicity. We investigated the possible involvement of dechlorination in CCl 3 NO 2 toxicity by considering its metabolism, inhibition of pyruvate and succinate dehydrogenases, cytotoxicity in cultured cells, and interaction with hemoproteins. In a newly discovered pathway, CCl 3 NO 2 is metabolized to thiophosgene, which is characterized as the cyclic cysteine adduct (raphanusamic acid) in the urine of mice. CCl 3 NO 2 inhibits porcine heart pyruvate dehydrogenase complex (IC‐50 4 μM) and mouse liver succinate dehydrogenase complex (IC‐50 13 μM), whereas its dehalogenated metabolites (CHCl 2 NO 2 and CH 2 ClNO 2 are more than 10 times less effective. The inhibitory potency of CCl 3 NO 2 for these dehydrogenase complexes is similar to that of captan, folpet, and dichlone fungicides (IC‐50 2–6 μM). CCl 3 NO 2 cytotoxity with Hepa 1c1c7 mouse hepatoma cells (IC‐50 9 μM) is not correlated with glutathione depletion. Mice treated intraperitoneally with CCl 3 NO 2 at 50 mg/kg but not with an equivalent dose of CHCl 2 NO 2 show increased concentrations of oxyhemoglobin in liver. The acute toxicity of CCl 3 NO 2 in mice is due to the parent compound or metabolites other than CHCl 2 NO 2 or CH 2 ClNO 2 and may be associated with inhibition of the pyruvate dehydrogenase complex and elevated oxyhemoglobin. © 1999 John Wiley & Sons, Inc. J Biochem Toxicol 14: 26–32, 2000