Hypercholesterolemia and the regulation of adrenal steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.
Plasma and adrenal cholesterol disposition have been examined to gain further insight into the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment decreases the diurnal peak in plasma corticosterone concentrations. TCDD induces an increase in plasma cholesterol concentration that is nearly complete on Day 2, at least 2 days before the most pronounced increase in adrenal cholesterol concentration (Days 4-6). This adrenal increase involves both free cholesterol and cholesterol esters, in contrast to the response to dietary hypercholesterolemia where only cholesterol esters increase. Although adrenocorticotropin (ACTH) does not increase adrenal mitochondrial cholesterol in normal rats (cholesterol turnover is faster than cholesterol uptake), this response changes between Days 6 and 9 after TCDD treatment such that ACTH then stimulates accumulation of mitochondrial cholesterol. This additional cholesterol is fully available to cytochrome P-450SCC, as judged both by active cholesterol metabolism in isolated mitochondria and by increased cholesterol-P-450SCC complex formation. The accompanying in vivo suppression of the peak plasma corticosterone concentration suggests a TCDD-induced inhibition of cholesterol side-chain cleavage (SCC). Consistent with this hypothesis, similar effects on adrenal mitochondrial cholesterol were produced by in vivo administration of the cholesterol side-chain cleavage inhibitor, aminoglutethimide, to ACTH-stimulated rats. Although the putative TCDD-induced inhibitory factor is apparently readily lost from mitochondria during preparation, inhibition may be retained in isolated cells. TCDD, therefore, affects adrenal cholesterol regulation by at least two mechanisms. Adrenal cholesterol content increases in part as a consequence of elevated plasma cholesterol, and cholesterol side-chain cleavage becomes partially inhibited in vivo.
D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D003345:Corticosterone / Q000097:blood*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D000616:Aminoglutethimide; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003345:Corticosterone