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, reversible
necrosis of the zona fasciculata 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.