6-beta-hydroxycortisol and Body-Weight

Treatment with carbamazepine (CBZ) affects cholesterol concentrations, but little is known about the precise nature and underlying mechanisms of changes in lipoprotein metabolism. We investigated prospectively the effects of CBZ on lipid metabolism in normolipemic adults. In 21 healthy males, lipoprotein and noncholesterol sterol concentrations were measured before and during treatment with CBZ for 70 +/- 18 days. Thirteen subjects underwent kinetic studies of apolipoprotein-B (ApoB) metabolism with the use of endogenous stable isotope labeling. Lipoprotein kinetic parameters were calculated by multicompartmental modeling. Significant increases in total cholesterol, in ApoB-containing lipoproteins [very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL)], and in triglycerides, but not in high-density lipoprotein (HDL), were observed. Lipoprotein particle composition remained unchanged. Mean fractional catabolic and production rates of ApoB-containing lipoproteins were not significantly different, although mean production rates of VLDL and IDL were substantially increased (+46 +/- 139% and +30 +/- 97%, respectively), whereas mean production of LDL remained unchanged (+2.1 +/- 45.6%). Cholestanol in serum increased significantly but not the concentrations of plant sterols (campesterol, sitosterol) and the cholesterol precursors (lathosterol, mevalonic acid). There was a significant correlation between the decrease in free thyroxine and the increase in IDL cholesterol. Treatment with CBZ increases mainly ApoB-containing lipoproteins. CBZ seems not to influence endogenous cholesterol synthesis or intestinal absorption directly. The increase is neither related to increased ApoB production nor to decreased catabolism but is rather due to changes in the conversion cascade of IDL particles, most likely as an indirect effect through a decrease in thyroid hormones.

Topics: Adult; Anticonvulsants; Arteriosclerosis; Body Composition; Body Weight; Carbamazepine; Cholestanol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Diet; Humans; Hydrocortisone; Intestinal Absorption; Lipoproteins; Male; Mevalonic Acid; Phytosterols; Sitosterols

Urinary 6 beta-hydroxycortisol is a useful, non-invasive index of microsomal mixed-function oxidase activity in man (review: [1]). Administration of phenobarbitone (40 mg/kg/day) for 4 days to male guinea-pigs, produced significant increases in hepatic microsomal cytochrome P-450 content and cytochrome P-450 reductase activity but did not increase 6 beta-hydroxycortisol excretion. The lack of relationship between urinary 5 beta-OHC excretion and microsomal mixed-function oxidase activity in the guinea-pig may be accounted for by the finding that 6 beta-hydroxycortisol itself undergoes extensive and variable metabolism in the guinea-pig.

Topics: Adrenal Cortex Hormones; Animals; Body Weight; Cytochrome P-450 Enzyme System; Cytochrome Reductases; Guinea Pigs; Hydrocortisone; Liver; Male; Microsomes, Liver; NADH Dehydrogenase; Organ Size; Phenobarbital