Role of thyroid state on induction by ciprofibrate of laurate hydroxylase and peroxisomal enzymes in rat liver microsomes.

The effects of hypothyroidism and hyperthyroidism upon liver microsomal omega-laurate hydroxylase activity (cytochrome P450 IV A1-dependent), peroxisome proliferation marker enzyme activities and acyl CoA oxidase (AOX) expression induced by ciprofibrate (2 mg/kg/day during 8 days) were studied in the male Wistar rat so as to clarify firstly the possible involvement of thyroid hormones in the modification of peroxisomal ciprofibrate-induced enzyme activities in relation to hepatic microsomal cytochrome P450 IV A1 induction, and secondly the possible direct effect of thyroid hormones on the gene expression of specific peroxisomal enzymes. No significant change was found in the ciprofibrate-induced omega-laurate hydroxylase activity in hypothyroid rats or in rats that had received a large dose of triiodothyronine (LT3), suggesting that the thyroid hormone does not interfere with the peroxisome proliferation process through such an indirect mechanism. The induction by ciprofibrate [2-(4-(2-2dichlorocyclopropyl)phenoxyl-2methyl-propion ic acid)] of mitochondrial alpha-glycerolphosphate dehydrogenase and microsomal bilirubin UDPGT was decreased about 3-fold and 1.5-fold, respectively, while the induction of peroxisomal AOX, carnitine acetyl transferase and enoyl CoA hydratase enzyme activities was decreased by 36%, 34% and 22% in thyroidectomized animals, as compared to euthyroid animals. However, no significant changes in the quantity of peroxisomal proteins and in the AOX mRNA level were noted. The administration of large doses of LT3 to normal rats decreased the peroxisomal ciprofibrate AOX enzyme induction with a marked concomitant decrease in the AOX mRNA level. This suggests that high doses of LT3 enhance the turnover of some specific mRNAs or down regulate the peroxisome proliferator receptor. Our results also do not exclude inhibition of catabolic activity towards AOX which depends on thyroid hormone.

Effects of simvastatin, a lipoprotein-lowering drug, on the hepatic enzymes involved in drug metabolism in the Wistar rat.

1. Simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, lowers the plasma cholesterol level and has been approved for treatment of hyperlipoproteinaemia. 2. Simvastatin has been studied for its effects on hepatic microsomal drug metabolism in rat. No induction of 7-ethoxyresorufin-O-deethylase (EROD), ethoxycoumarin-O-deethylase (ECOD) and of UDP-glucuronosyltransferases were found, in vitro, after administration of 0.5, 1.5 and 10 mg/kg per day for 22 days. 3. Epoxide hydrolases (microsomal and cytosolic) were also unchanged after treatment with simvastatin. 4. No increase of the palmitoyl CoA oxidase activity or of mitochondrial glycerol phosphate dehydrogenase activity occurred. 5. Fatty acid distribution in rat liver microsomal phosphatidylcholines showed a significant decrease of C16:1 and a significant increase of C20:4 acids.

Comparative and simultaneous effects of simvastatin and ciprofibrate on plasma lipid parameters and upon hepatic drug metabolizing and peroxisome proliferation marker enzymes in the male Wistar rat.

The effects of an associated treatment with Ciprofibrate and Simvastatin upon plasma lipid parameters, liver Mixed Function Oxidases enzymes and peroxisomal markers have been studied in male Wistar rats. The association was efficient upon triglycerides, but not upon cholesterol. The inducive and proliferative effects commonly exerted by Ciprofibrate (5 mg/kg/day) were not significantly modified by the simultaneous treatment with Simvastatin (10 mg/kg/day). The increase of the seric alanine amino transferase activity was however much more pronounced after the associated treatment than after single administration of Ciprofibrate or Simvastatin.

Nutritional factors of microsomal enzymatic induction: influence of lipidic components of the diet.

We compared the ability of two different diets containing 6 per cent of maize oil and 6 per cent of fish oil to modify: firstly the enzyme induction by phenobarbital and secondly the phenobarbital hydroxylation by the liver either in vivo or during in vitro perfusions. The presence of fish oil in the diet increased the cyt P 450 content and the bilirubin glucuronosyl transferase activity. The two induction effects promoted by the association of the phenobarbital treatment and the eating of the fish oil were not additive and it was found that the phenobarbital induction effect was decreased by the fish oil consumption. Phenobarbital and p-hydroxyphenobarbital kinetics were different in the two groups of animals. Phenobarbital was more slowly eluted in the fish oil fed than in the maize oil fed rats while p-hydroxyphenobarbital was more slowly eluted by the fish oil-fed rat livers.

[Influence of thyroid status on microsomal and peroxysomal enzyme induction by fibrates in rats]. / Influence des états thyroïdiens sur l'induction des enzymes microsomales et peroxysomales par les fibrates chez le rat.

The influence of thyroid hormones upon the inductive effects on microsomal enzymes and the hepatic proliferation produced by different fibrates was studied in the male rat. A pharmacological dose of triiodo-L-thyronine significantly lowers the total cytochrome P450 content induced by some equi-effective doses of clofibrate, ciprofibrate, bezafibrate and fenofibrate. The ethoxycoumarin O-deethylase activity (ECOD) is concomitantly decreased. On the contrary, L-T3 accentuates the specific inductive effect of fibrates on bilirubin-UDPGT activity. Hypothyroid has little or no influence upon the effect of fibrates towards cytochrome P450 content and ECOD activity. On the other hand, this thyroid status significantly lowers the CN- palmitoyl coenzyme A dehydrogenase, which is a marker enzyme of the peroxisome proliferation caused by the different fibrates. These results indicate a possible modulation of thyroid hormones within the fibrates induction mechanism in the rat.

Inductive effects of fenofibrate and metabolism of phenobarbital.

The inductive effects of fenofibrate (FF) and phenobarbital (PB) were investigated in male Wistar rats. FF treatment produced an inductive effect on liver weight, cytochrome P450 content, and aniline hydroxylase (AH) and bilirubin UDP-glucuronosyltransferase (UDP-GT) activities in liver microsome fraction. PB and FF inductive effects were additive on liver weight but were not additive on P450 microsomal concentrations. On the contrary, FF administration decreased the inductive effect of PB on bilirubin UDP-GT activity. When FF and PB treatment were coupled, plasma and liver PB concentrations were not affected, whereas OHPB concentrations, especially in liver homogenate, were greatly decreased. Thus it can be concluded that the production of OHPB from PB was probably not accelerated, but the elimination of OHPB, the main metabolite of PB, was considerably enhanced. These results are to be compared with recent reports of structure-dependent induction of bilirubin glucuronidation by arylcarboxylic acids chemically related to clofibrate.

[Ingestion of soybean epoxide oil. Effects on monooxygenases, epoxide hydrolase and activities of UDP glucuronosyltransferases in hepatic microsomes of the rat]. / Ingestion d'huile de soja époxydée. Effet sur les monooxygénases, l'époxyde hydrolase et les activités UDP glucuronosyltransférases des microsomes hépatiques chez le rat.

The effect of peroxidized soybean oil in the diet of male Wistar rats was studied on hepatic drug metabolizing enzymes and their phenobarbital induction and compared to that of natural soybean diet in the same conditions. No hepatomegaly or increase in serum transaminases occurred, however growth was inhibited after ingestion of peroxidized soybean oil. In addition, the protein biosynthesis of epoxide hydrase determined by immunochemistry was largely stimulated by this treatment; but the corresponding activity measured with benzo(a)pyrene 4-5 oxide as a substrate was increased in weaker proportions. This induction was limited to epoxide hydrolase only, since the enzymes of phase one were not affected and UDP glucuronosyltransferase activities toward group I substrates were randomly activated. The induction of epoxide hydrolase may affect only one or several isoforms of the membrane enzyme which are not necessarily specific to benzo(a)pyrene 4-5 oxide activity determination of the enzyme.

[Effects of 3,5,3'-triiodo-L-thyronine on the enzymes responsible for the metabolism of xenobiotics in the rat after increase in the dietary supply of cholesterol]. / Effets de la 3,5,3'-triiodo-L-thyronine sur les enzymes responsables du métabolisme des xénobiotiques chez le Rat aprés augmentation de l'apport alimentaire en cholestérol.

A cholesterol rich diet fed to rats was found to increase the cytochrome P 450 content in hepatic microsomes. Furthermore, the variations of the same parameters promoted by 3,5,3'-triiodo-L-thyronine were strongly reduced in cholesterol supplemented rats. Cholesterol prevented the inducing effects of phenobarbital but did not oppose its decreasing effect on maximal fluorescence of ANS and PNA introduced into the microsome suspensions.

[Influence of 3,5,3'-triiodo-L-thyronine on the hepatic enzyme activities responsible for the metabolism of xenobiotics during the development of the chick embryo]. / Influence de la 3,5,3'-triiodo-L-thyronine sur les activités enzymatiques hépatiques responsables du métabolisme des xénobiotiques pendant le développement de l'embryon de Poulet.

The influence of thyroid hormones on microsomal drug metabolizing enzymes was studied in hypothyroid newborn rats and chick embryos. Administration of 3,5,3'-triiodo-L-thyronine strongly decreased the microsomal cytochrome P 450 content in hypothyroid new-born rats and thus could render the rat pup more susceptible to hepatotoxicity from drugs. The drug metabolizing system in 20 days old chick embryos was less sensitive to the effects of thyroid hormone, but administration of phenobarbital was accompanied by a strongly induction effect on microsomal enzyme activities.

[Effects of the ingestion of oxidized fish oils on hepatic microsomal enzyme activities and membrane fluidity in rats. Influence of tocopherol overload]. / Effets de l'ingestion d'huiles de poisson oxydées sur l'activité des enzymes microsomales hépatiques et la fluidité membranaire chez le rat. Influence d'une surcharge en tocophérol.

Rats fed a dietary peroxidized fish oil showed an increase in cytochrome P-450 content and ethoxy-coumarin deethylase (ECDE) activity in liver microsomes. Administration of DL-alpha-tocopherol led to different effects according to the extent of the peroxidation in the fish oil. In rats fed a de-peroxidized oil, the inductive effect of phenobarbital on UDP-glucuronosyltransferase (UDGPT) activity was depressed by tocopherol. By the same time, induction of P-450 and ECDE remained unchanged, that of epoxide hydrase slightly increased. By contrast tocopherol strongly potentiated the inductive effect of phenobarbital toward UDPGT activity (group I substrates) in rats fed the peroxidized fish oil. The modification of the inductive effect of phenobarbital in combination with tocopherol on UDPGT activities was concomitant with an increase in seric transaminase activity and with a reverse effect as revealed from the study of the rate of fluorescent probes penetration in microsomes. The possible toxicity of the strong dose of tocopherol is discussed.

[Effects of several antilipemic agents on the activity of liver microsomal enzymes]. / Effets de divers hypolipoprotéinémiants sur l'activité des enzymes microsomales hépatiques.

Male Wistar rats were treated daily for 7 days with clofibrate (250 mg/kg/d), benfluorex (50 mg/kg/d), tiadenol (200 mg/kg/d), nicoclonate (100 mg/kg/d) or hexanicit (50 mg/kg/d). The cytochrome P 450 level and ethoxycoumarin deethylase activity (ECDE) in liver microsomes were markedly increased by administration of clofibrate and slightly increased by tiadenol. Benfluorex only increased the activity of ECDE and nicoclonate and hexanicit had no effect. Clofibrate, tiadenol and benfluorex increased the activity of microsomal bilirubin UDP-glucuronosyltransferase. On the other hand, the nicotinic derivatives were ineffective. Tiadenol clearly enhanced the inductive effects of phenobarbital.

[Effects of ingestion of oxidized fish oils on membrane fluidity, and the activity of hepatic microsome enzymes in rats. Influence of vitamin A overload]. / Effets de l'ingestion d'huiles de poissons oxydées sur la fluidité membranaire, et l'activité des enzymes microsomales hépatiques chez le rat. Influence d'une surcharge en vitamine A.

Oxidized fish oil (OFO) feeding is followed in the rat by the increase of vitamin A plasmatic level, and modifications of microsomal membranes (decrease of fluorophore ANS fixation). This inhibit the microsomal increase of cytochrome P 450, mixed function oxidase (MFO), any UDP-glucuronosyl transferases (group I) induced by phenobarbital treatment. On the other hand, vit A over load modify the microsomal structure of the opposite way (increase of ANS fixation). This effect is enlarged when OFO is added. In this case cyt P 450 is decreased. It seems that the magnification of vit. A effect is similar to increased microsomal membrane lability by oxidized fish oil addition.

[Effect of thyroid status on microsomal enzymes during liver regeneration in the rat]. / Influence de l'état thyroïdien sur les enzymes microsomales au cours de la régénération hépatique chez le rat.

The effects of thyroid status upon cyt. P 450 concentration and ethoxycoumarin deethylase, benzopyrene hydroxylase and UDP-glucuronosyltransferase activities in the liver microsome fraction were far more important in partially hepatectomized rats than in control animals. The partial hepatectomy simultaneously lowered the MFO enzymes activities in the hepatic microsome fraction and made them more sensitive to thyroid hormones effects.

[Effect of carbamate pesticides on the induction of hepatic enzymes of the rat and on the microsomal phospholipid changes]. / Etude de l'influence des pesticides carbamines sur l'induction des enzymes hépatiques du rat et sur les modifications des phospholipides microsomaux.

The influence of two carbamine pesticides i.e., manebe and carbaryl upon the hepatic microsomal enzymes induction in the rat was studied. Both substances, when administered by themselves, affect only slightly liver weight, P 450 cytochrome rates and bilirubin glucuronosyltransferase, in the microsome fraction of the hepatic homogenate. It seems, however, that carbaryl is involved in producing a slight induction, whereas manebe acts inversely. Yet, manebe changes largely the induction effects of phenobarbital when associated with the latter. In the animal treated simultaneously with manebe and phenobarbital, the increase in the rate of hepatic microsomal P 450 cytochrome as well as the variations in the distribution of fatty acids in phospholipids, are significantly lower than in the animal solely treated with phenobarbital.

Etude de l'influence des pesticides carbamines sur l'induction des enzyes hepatiques du rat et sur les modifications des phospholipides microsomaux. / Effect of carbamate pesticides on the induction of hepatic enzymes of rats and on the microsomal phospholipid changes

Se estudio la influencia de dos pesticidas carbaminados: El Manebe y el Carbaryl sobre las enzimas de los microsomas hepaticos que son inducibles en la rata. Se encontro que las dos substancias ensayadas por si mismas tienen efectos de poca importancia en el peso del higado y en el tenor de citocromo P 450 y de bilirubina glucuronosil transferasa de la fraccion microsomal del homogeneizado hepatico. Parece ser, sin embargo, que el Carbaryl provoca una pequena induccion mientras que el Manebe produce un efecto inverso. Por otra parte, el Manebe modifica muy sensiblemente los efectos inductores del fenobarbital al asociarse a este ultimo. Asi, en el animal tratado simultaneamente con Manebe y fenobarbital, el incremento del tenor de citocromo P 450 hepatico, asi como las variaciones de la reparticion de los acidos grasos en los fosfolipidos son netamente de menor importancia que en los animales tratados unicamente con el fenobarbital