Toxicity, ultrastructural effects, and metabolic studies with 1-( o-chlorophenyl)-1-( p-chlorophenyl)-2,2-dichloroethane( o,p′-DDD) and its methyl analog in the guinea pig and rat

Abstract

Effects of 1-( o-chlorophenyl)-1-( p-chlorophenyl)-2,2-dichloroethane ( o,p′-DDD) (Lysodren; Mitotane) (I) and 1-( o-chlorophenyl)-1-( p-chlorophenyl)-2,2-dichloropropane (Mitometh) (II) were investigated. Ultrastructural and toxicity studies were conducted with male Hartley outbred guinea pigs given 300 mg/kg/day ip for 14 days. Profound mitochondrial damage in the guinea pig adrenal cortex, an index of Lysodren's action as a cancer chemotherapeutic, was also seen in Mitometh-treated animals. This effect produced selective, reversible necrosis of the zona fasiculata and zona reticularis with swelling, disrupted cristae, and organelles destroyed in the mitochondria from these areas. Yet guinea pigs given Mitometh tolerated the drug better than those given an equivalent amount of Lysodren. In general the animals treated with Mitometh showed less alopecia, diarrhea, and weakness. The only deaths recorded in our study were in the Lysodren group. In addition po administration of these two drugs to male Sprague-Dawley rats and male Hartley guinea pigs for 4 days allowed for a direct comparison of urinary metabolites. Metabolites were identified from urine extracts by computerized mass spectrometry interfaced with capillary gas chromatography. Both compounds were shown to undergo dehydrohalogenation and side-chain cleavage to a limited extent; however, only Lysodren afforded side-chain oxidation metabolites. In fact, the dominant metabolite from Lysodren biotransformation was the corresponding carboxylic acid o,p′-DDA (III). On the other hand, Mitometh resisted side-chain oxidative metabolism and was less toxic than Lysodren. Therefore, when given to guinea pigs and rats, Mitometh had Lysodren-like biologic activity, did not undergo rapid inactivation, and was less toxic than Lysodren. Mitometh represents a potential alternative to Lysodren which should be investigated further for its possible use in the treatment of adrenal cortical carcinoma and Cushing's syndrome.