A time course investigation of vitamin A level and lipid composition of the liver endoplasmic reticulum in rats following treatment with congeneric polychlorobiphenyls.

The drug metabolizing enzyme activities, the vitamin A content and the fatty acid composition in the endoplasmic reticulum membrane were studied in rat liver after a single injection of the polychlorobiphenyls (PCBs) 3,3',4,4'-tetrachlorobiphenyl [(3,4)2Cl] or 2,2',4,4',5,5'-hexachloro-biphenyl [(2,4,5)2Cl], 300 mumol/kg each. The microsomal vitamin A level was markedly lowered 3 days after treatment with (3,4)2Cl, a coplanar type inducer of cytochrome P-450. A marked increase in microsomal AHH and UDPGT activities occurred within 3 days after injection of (3,4)2Cl whereas (2,4,5,)2Cl treatment enhanced APDM activity only. Arachidonic, stearic and linoleic acid microsomal contents were enhanced by the two congeners. (3,4)2Cl caused the proportion of docosahexaenoic acid to decrease. No highly significant correlation was found between the vitamin A content and lipid components in the microsomal membrane. However, the vitamin A level was inversely related to the activities of drug metabolizing enzymes induced by coplanar compounds (cytochrome P-450 towards benzo[a]pyrene and UDP glucuronosyl transferase towards 4-nitrophenol).

Effects of prototypic PCBs on benzo[a]pyrene mutagenic activity related to vitamin A intake.

The effects of vitamin A dietary intake (2 and 20 IU */g of food) on the mutagenic activity of benzo[a]pyrene (B(a)P) toward Salmonella typhimurium (TA98) were studied either in control rats or in animals treated by the PCB congeners 2,4,5,2',4',5'-hexachlorobiphenyl [2,4,5)2Cl) and 3,4,3',4'-tetrachlorobiphenyl [3,4)2Cl). (3,4)2Cl (a planar compound) strongly increased B(a)P monooxygenase (B(a)PMO) activity and glutathione transferase, (2,4,5)2Cl (a non-planar PCB) was a strong inducer of epoxide hydrolase and a weak inducer of B(a)PMO. Enzyme induction was not modified by changes in vitamin A dietary intake. A higher mutagenic effect was observed in the (3,4)2Cl group than in the (2,4,5)2Cl one. This could be related to the specific form of cytochrome P-450 induced by (3,4)2Cl. In the untreated animals, the activation of B(a)P was higher in the 2-IU group than in the 20-IU one. Conversely, in PCB-treated rats the mutagenic activity of B(a)P was higher in the 20-IU group than in the 2-IU one. PCB induction increased the liver content of vitamin C in both the 2-IU and the 20-IU groups but only increased the glutathione levels in the 2-IU groups. This suggests that glutathione content in cellular fractions may be one of the determining parameters for the mutagenic activity of B(a)P.

A time-course investigation of vitamin A levels and drug metabolizing enzyme activities in rats following a single treatment with prototypic polychlorinated biphenyls and DDT.

Xenobiotics previously characterized as selective inducers of drug-metabolizing enzymes were chosen to probe possible relationships between enzyme induction and vitamin A metabolism. Liver, kidney and serum retinol and retinyl palmitate levels were investigated in male Sprague--Dawley rats receiving a single i.p. injection of the polychlorinated biphenyls (PCBs), 2,2',5,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl or 2,2',4,4',5,5'-hexachlorobiphenyl (300 mumol/kg) or 1,1,1-trichloro-2,2-bis-(4-chlorophenyl)-ethane (DDT) (150 mumol/kg). While 2,2',5,5'-tetrachlorobiphenyl, a weak or non-inducer, and 2,2',4,4',5,5'-hexaclorobiphenyl and DDT, phenobarbital-type inducers of cytochrome P-450, led to no reduction in total vitamin A content of liver or kidney during the 7 day time-course, administration of 3,3',4,4'-tetrachlorobiphenyl, a toxic PCB and a potent 3-methylcholanthrene-type inducer of cytochrome P-450, resulted in progressively lowered liver vitamin A levels (to 40% of control values by day 7). During this time, kidney total vitamin A content increased 3-fold. The increase in kidney vitamin A (due primarily to increased retinol content) was only equal to 1/40 of total vitamin A which had disappeared from the liver. Although 3,3',4,4'-tetrachlorobiphenyl specifically induced certain drug-metabolizing enzyme activities, e.g. aryl hydrocarbon hydroxylase and UDP-glucuronosyltransferase (toward 4-nitrophenol), no highly significant correlations were found among the vitamin A levels and drug-metabolizing enzyme activities in the liver (aminopyrine N-demethylase, aryl hydrocarbon hydroxylase, aldrin epoxidase, microsomal epoxide hydrolase, UDP-glucuronosyltransferase toward 4-nitrophenol, glutathione transferase toward 1-chloro-2,4-dinitrobenzene and cytochrome P-450 content) as determined by multiple linear regression analysis.

Cyclosporine administration decreases liver vitamin A stores in normal and vitamin A-deficient rats.

Thirty-four Wistar rats were fed a marginal or normal vitamin A diet and received daily for 14 days an intragastric intubation of oil supplemented with 0, 20, or 60 mg X kg-1 of cyclosporine A. The hepatic content and concentration of vitamin A were significantly decreased by cyclosporine treatment, whereas no modification occurred in kidney or serum vitamin A levels. No induction of hepatic cytochrome P-450 was observed in treated animals. These results suggest that cyclosporine interferes with vitamin A stores; thus, vitamin A supplementation may be useful in patients receiving cyclosporine therapy. Drug-metabolizing enzymes, which are cytochrome P-450 dependent, did not seem to be involved in the hepatic vitamin A decrease observed.