Differential action of thyroid hormones and chemically related compounds on the activity of UDP-glucuronosyltransferases and cytochrome P-450 isozymes in rat liver.

The effect of thyroid hormones and chemically related compounds, on the activity of UDP-glucuronosyltransferases (EC 2.4.1.17) and cytochrome P-450-dependent monooxygenases in rat liver microsomes was investigated. The animals were thyroidectomized and treated with different doses of the drugs for 3 weeks. Opposite effects were observed depending on the isoenzyme of UDP-glucuronosyltransferase considered. While 3,3',5-triiodo-L-thyronine, 3,3',5-triiodothyroacetic acid, 3,3',5-triiodothyropropionic acid, isopropyldiiodothyronine and L- and D-thyroxine strongly increased 4-nitrophenol glucuronidation in a dose-dependent fashion, they decreased markedly bilirubin glucuronidation. However, the activity toward nopol, a monoterpenoid alcohol, was not significantly changed regardless of which compound or dose was used. Variation of UDP-glucuronosyltransferase observed with 4-nitrophenol and bilirubin was related to the thyromimetic effect of the drugs estimated from the increase in alpha-glycerophosphate dehydrogenase. Thyronine and 3,5-diiodo-L-tyrosine, which did not enhance this activity, also failed to affect glucuronidation. Variations in UDP-glucuronosyltransferase activity were more likely due to changes in protein expression rather than changes in enzyme latency, since lipid organization of the microsomal membrane, as estimated from the mean anisotropy of 1,6-diphenyl-1,3,5-hexatriene by fluorescence polarization was not significantly modified by the drug administration. Although some of the drugs could significantly decrease the triacylglycerol and cholesterol contents in plasma, all failed to affect lauric acid hydroxylation. The activities of catalase, palmitoyl-CoA dehydrogenase (CN- insensitive) and carnitine acetyltransferase in the fraction enriched in peroxisomes were also not significantly affected by treatment with the thyroid hormone LT3. In contrast, the activity of 7-ethoxycoumarine O-deethylase was increased by large doses of thyronine and by 3,3',5-triiodothyropropionic acid. The concentration of total cytochrome P-450 was decreased in a dose-dependent fashion by all the compounds used, except thyronine. Finally, significant correlations were observed between glucuronidation of bilirubin and 4-nitrophenol and the content in cytochrome P-450. This suggests a possible coordinate regulation of the two processes, which depends on the physicochemical characteristics of the thyroid hormones and related compounds.

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.

Liver microsome phospholipids and cytochrome P.450 concentration in phenobarbital treated rats fed on different diets.

Liver microsomal concentration of cytochrome P.450 is increased in animals which are fed diets rich in polyunsaturated fatty acids. On the other hand, the effects of phenobarbital are more important when the dietary fat is more unsaturated. The unsaturation index in liver microsomal phosphatidylcholines depends on the unsaturation of the dietary fats. The treatment with phenobarbital constantly results in a decrease of the unsaturation index of fatty acids both in lecithins and cephalins. The importance of the liver microsomal cytochrome P.450 increase and the importance of the unsaturation index decrease in liver microsomal lecithins, both promoted by phenobarbital, are in good agreement.

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.

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.

[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.

[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.

[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.

[Effect of various 2-methyl-(4'-chlorobenzoyl)-4-phenoxy)-2 propionic acid (LF 153) analogs on the respiratory activity of rat liver mitochondria]. / Inluence de quelques analogues structuraux de l'acide méthyl-2 [(chloro-4' benzoyl)-4 phénoxyl]-2 propionique (LF 153) sur l'activité respiratoire de mitochondries hépatiques de rat.

Seven analogs of methyl-2 [chloro-4' benzoyl)-4 phenoxy]-2 propionic acid, (LF 153) have been tested for their effects on respiration and phosphorylation of rat liver mitochondria suspensions. They differ from one another by the sort of binding between both aromatic cycle as well as by the nature and position of the halogenated substitutions and alpha methylation in the propionic chain. All the compounds which have been tested acted as inhibitors of the electron transport chain and uncouplers of phosphorylations.