Morphogenesis of a Zone-Specific Adrenocortical Cytotoxicity in Guinea Pigs Administered PD 132301-2, an Inhibitor of Acyl-CoA: Cholesterol Acyltransferase

Abstract

PD 13230 1-2, a novel inhibitor ofacyl-CoA: cholesterol acyltransferase, is adrenotoxic to several laboratory animal species. Morphogenesis of a zona fasciculata-specific cytotoxicity was evaluated in male Hartley guinea pigs administered 100 mg/kg of PD 132301-2 for up to 7 days. Reversibility of adrenal effects was assessed after a 14-day drug withdrawal period (day 21). Serum cortisol concentrations were determined under basal conditions and after administration of adrenocorticotrophic hormone (ACTH) on days 1, 2, 4, 7, and 2 1. Isolated foci of cortical cell degeneration and necrosis were apparent in outer zona fasciculata by 2 hr and throughout the zona fasciculata at 6 hr. Early degenerative ultrastructural changes included aggregation of smooth endoplasmic reticulum (SER), variable condensation of mitochondria1 matrices and swelling of cristae, partitioning of organelles, autophagosome formation, and disruption of lipid globules. Lesions progressed to locally extensive or diffuse zonal necrosis on days 1 and 2 and near complete ablation of zona fasciculata by day 4. Fasciculata cells remaining on day 4 had reduced numbers and increased size of lipid globules, increased lysosomes, and, occasionally, aggregates of SER and mitochondria. On day 7, SER proliferation and lipid depletion were apparent in remaining cells. ACTH responses were attenuated 24 hr after the first dose, and reduction in basal cortisol levels were seen by 24 hr after the second dose with both effects maximal on day 7. After a 14-day withdrawal period, ACTH responses and adrenal morphology returned to normal. It was concluded that PD 132301-2 induced rapid, reversible, zone-specific, morphologic, and functional adrenocortical effects. Furthermore, mitochondria and SER represented early subcellular targets of toxicity.

Structure-Activity Relationships of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and Analogues as Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase.

“…In addition, the hypocholesterolemic activity of n-alkyl derivatives increased according to the length of the alkyl chain, and n-octyl (27), n-nonyl (28), and n-decyl (29) derivatives produced significant hypocholesterolemic activity when administered as a dietary admixture at a concentration of 0.005%. Although 23 and 24 inhibited ACAT in a more striking fashion than 29, these derivatives did not exhibit hypocholesterolemic activity.…”

“…For these derivatives, unlike those with a 2,4-dimethyl residue in the C-phenyl ring (25)(26)(27)(28)(29), the drug efficacy did not increase according to the length of the nalkyl chain at R 2 in the A-phenyl ring, and the n-octyl derivative (45) had the highest level of hypocholesterolemic activity.…”

“…Clinical development of ACAT inhibitors, however, has not been successful, 25,26) be- [27][28][29][30][31][32][33][34][35][36][37][38] Recently, ACAT has been classified into two isozymes, ACAT-1 and ACAT-2, and research suggests that they differ in terms of their distribution in the body. [39][40][41][42][43] Two reasons are believed to be involved in why the numerous ACAT inhibitors that have been developed thus far have not been clinically successful.…”

“…With modification of region A in the molecule (Fig. 1), phenylpiperamides (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(42)(43)(44)(45)(46) were prepared by amidation of 8 with corresponding phenylpiperazine, followed by alkylation with appropriate halide.…”

Adrenocortical LDL receptor function negatively influences glucocorticoid output

“…Although most studies on the effect of lipoproteins on adrenal function have focused on steroidogenesis, it should be acknowledged that cholesterol is essential for adrenal growth in vivo (Dominick et al 1993). Based on the fact that LDLRs on adrenocortical cells are able to effectively clear cholesterol-rich LDL particles upon ACTH administration in vivo (Kovanen et al 1980), we anticipate that the cholesterol derived from LDL is rather used for non-steroidogenic adrenal functions, including adrenocortical cell proliferation.…”