Prevention of butylated hydroxytoluene-induced lung damage by diethyldithiocarbamate and carbon disulfide in mice.
Diethyldithiocarbamate (DTC) and carbon disulfide (CS2), at nearly equimolar doses (po), prevented mice from lung injury induced by butylated hydroxytoluene (BHT), as evidenced by suppression of increased lung weight and total DNA content as well as by histopathologic observations. CS2 pretreatment dose dependently decreased the amount of covalently bound [ring-14C]BHT to lung macromolecules in vivo. A slight, but significant, loss of lung GSH observed early after BHT administration was also prevented. The lung microsomal fraction exhibited NADPH-dependent covalent binding of BHT in vitro; this was inhibited completely by carbon monoxide and slightly by SKF-525A. This NADPH-dependent binding was suppressed in lung microsomes isolated from CS2-treated mice. CS2 also reduced various drug metabolizing enzyme activities and the cytochrome P-450 content of the lung microsomal fraction. These results support the metabolic activation hypothesis for BHT-induced lung damage, and the preventive action of CS2 and DTC may be due to an inhibition of this bioactivation step. Possible sites of the metabolic activation of BHT and its inhibition by CS2 are discussed.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002246:Carbon Disulfide / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; D002084:Butylated Hydroxytoluene; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; D010089:Oxidoreductases, N-Demethylating; D002246:Carbon Disulfide