Differential toxicity of an inhibitor of mitochondrial respiration in canine hepatocytes and adrenocortical cell cultures.
PD132301-2, a novel inhibitor of acyl-CoA: cholesterol acyltransferase, was previously shown to be an inhibitor of mitochondrial respiration and an adrenal toxicant in several species. To investigate potential mechanisms of tissue-specific toxicity in vivo, dog adrenocortical and hepatocyte cell cultures were exposed to 0.01-30 mum PD132301-2 for 0-24 hr. Cell viability was assessed by neutral red uptake or release assays. Cytotoxicity was observed in adrenocortical cells at 0.01 mum or above after 2hr of exposure, while 30 mum was not toxic to hepatocytes after 24 hr of exposure. Decreases in adrenocortical cell viability were attenuated in the presence of 20 mm fructose, a glycolytic substrate, and fructose protection was in turn blocked by the glycolytic inhibitor NaF (1 mm). In contrast, PD132301-2-induced hepatocellular toxicity was evident only following pretreatment with NaF or metyrapone, a broad-spectrum cytochrome P-450 inhibitor. With either co-treatment, hepatocyte viability was reduced 50% after 6 hr at 1 mum or more PD132301-2. These data indicate that the relative sensitivity of adrenocortical cells to the cytotoxic effects of PD132301-2 may be due, in part, to their relative lack of the metabolic detoxification and glycolytic reserve capacities that appear to protect hepatocytes from PD132301-2 toxicity.
Vernetti
L A
LA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Macdonald
J R
JR
Pegg
D G
DG