Vitamin A modulates the effects of thyroid hormone on UDP-glucuronosyltransferase expression and activity in rat liver.

We studied the influence of thyroid hormones and vitamin A status on the regulation of UDP-glucuronosyltransferase (UGT) expression and the glucuronidation of thyroid hormones by UGTs. For this, we used an original model of rats fed with different vitamin A diets and implanted subcutaneously by osmotic minipumps delivering vehicle or thyroid hormones, which permitted the control of plasma thyroid hormone concentrations. The activity and expression of family 1 UGTs are correlated and were significantly modified by both thyroid status and amounts of retinol in the diet.

Influence of vitamin A status on the regulation of uridine (5'-)diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A6 expression by L-triiodothyronine.

The uridine (5'-)diphosphate-glucuronosyltransferases (UGT) are involved in the phase II of various xenobiotics and endogenous compounds. They are responsible for glucuronidation of many substrates, especially including bilirubin (UGT1A1) and phenolic compounds (UGT1A6). We previously showed that the expression of both isoforms is regulated at the transcriptional level by thyroid hormone in rat liver.

6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.

Prevention of allograft transplant rejection by the immunosuppressive 6-thiopurine drug azathioprine is limited by haematological toxicity (leucopenia or agranulocytosis). This toxicity is particularly apparent in subjects with low thiopurine methyltransferase activity (TPMTase) phenotype (1% in the Caucasian population). The thiopurine derivative 6-mercaptopurine is the active metabolite of azathioprine, and it would be of interest to measure, after validation of plasma measurements, the mean values of the pharmacokinetic parameters in transplant patients with high or intermediate TPMTase phenotypes (85 and 14% of the Caucasian population, respectively).

Comparative quantification of two hepatic UDP-glucuronosyltransferase bilirubin isoforms mRNAs in various thyroid states in rat.

The study was designed to compare the effects of 3,5,3' triiodo-L-thyronine (L-T3) on the levels of hepatic mRNAs encoding two UDP-glucuronosyltransferase bilirubin isoforms (UGT1*1 and UGT1*0) in rats, by reverse transcription and quantitative polymerase chain reaction (RT-PCR). The administration of L-T3 decreased the UGT1*O mRNA by 2.2-fold and that of UGT1*1 by only 1.

Opposite regulation of bilirubin and 4-nitrophenol UDP-glucuronosyltransferase mRNA levels by 3,3',5 triiodo-L-thyronine in rat liver.

The effects of 3,3',5 triiodo-L-thyronine (L-T3) on the constitutive levels of hepatic mRNA encoding two UDP-glucuronosyltransferase (UGT) isoforms implicated in the glucuronidation of planar phenolic substrates (UGT1*06) and bilirubin (UGT1*0) were investigated in rat liver. The amount of UGT mRNA was quantitated by reverse transcription and amplification methods (RT-PCR). Treatment with L-T3 significantly increased UGT1*06 and decreased UGT1*0 mRNA levels by 41% and 54%, respectively.

In vitro glucuronidation of peroxisomal proliferators: 2-ethylhexanoic acid enantiomers and their structural analogs.

In order to investigate the glucuronidation of 2-ethylhexanoic acid (2-EHA), a metabolite of the plasticizer di-(2-ethylhexyl) adipate, by liver microsomes of several mammalian species including man, a gas chromatography method for the quantification of the corresponding glucuronides was developed. The variation coefficients for intra- and interassay repeatability were less than 3 and 7%, respectively. The rat liver UDP-glucuronosyl-transferase (UGT) presented similar Km and Vmax toward the two enantiomers.

Characterization of the in vitro glucuronidation of flurbiprofen enantiomers.

To investigate the glucuronidation of the R- and S-enantiomers of the nonsteroidal antiinflammatory drug, flurbiprofen, by liver microsomes of several mammals, including humans, a new and reliable HPLC method for the separation and quantification of the corresponding diastereoisomeric glucuronides has been developed. Interspecies comparison revealed that the glucuronidation of flurbiprofen was highly efficient with liver microsomes of humans, monkeys, rats, and guinea pigs (in decreasing ranking order). Gunn rats, which present a genetic defect in the bilirubin UDP-glucuronosyltransferase (UGT) isoforms, were still able to glucuronidate the drug.

[Determination of serum or plasma alpha-tocopherol by high performance liquid chromatography: optimization of operative models].

A previous multicentric study set up by the Société française de biologie clinique has emphasized the usefulness of a standardized procedure for the determination by high performance liquid chromatography of alpha-tocopherol in serum or plasma. In our study, we have tested every step of the different published procedures: internal standard adduct, lipoprotein denaturation and vitamin extraction. Reproducibility of results was improved by the use of tocol as an internal standard when compared to retinol or alpha-tocopherol acetates.

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.

Cyclosporine determinations in heart and liver transplant recipients: comparison of HPLC and FPIA methods on whole blood and plasma.

One hundred and eighty five whole blood samples were analysed for cyclosporine levels by fluorescence polarization immunoassay (FPIA) and high performance liquid chromatography (HPLC). 123 came from 4 heart transplant recipients (mean age +/- SD: 47.50 +/- 20.

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).

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.

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.

Methods of theophylline assay and therapeutic monitoring of this drug.

The purpose of this article is to review various analytical methods of monitoring plasma theophylline. This article was investigated by the "Drug Commission" of SFBC (Société Française de Biologie Clinique). The primary objective is to provide the "know-how", particular for this analysis, which allows the choice between various analytical methods available: immunochemical or physiochemical ones.

[Influence of thyroid status on microsomal and peroxysomal enzyme induction by fibrates in rats].

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.

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.

[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].

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 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].

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.

[Ingestion of soybean epoxide oil. Effects on monooxygenases, epoxide hydrolase and activities of UDP glucuronosyltransferases in hepatic microsomes of the 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.

Pharmacokinetics of bupivacaine after axillary brachial plexus block.

Severe cardiovascular complications have been associated with regional anesthesia using bupivacaine. Furthermore, in our practice, axillary brachial plexus block is commonly used for surgical emergencies of the hand in out-patients. The pharmacokinetics parameters: peak height (Cmax), peak time (tmax), half life of plasma elimination (t1/2), total apparent clearance (Cl), mean time of plasma retention (t) were studied in 20 male and female patients (mean age 35 and 32 years) receiving axillary local anesthesia by bupivacaine (BU) only (A group = 100 mg), B group BU = 200 mg, or BU + lidocaine (LI) (C group = BU 100 mg + LI 200 mg), plasmatic BU and LI were simultaneously measured by HPLC method.

[Effects of the ingestion of oxidized fish oils on hepatic microsomal enzyme activities and membrane fluidity in rats. Influence of tocopherol overload].

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.

Modulation of UDPglucuronosyltransferase activity in rats by dietary lipids.

Male Wistar rats were fed for 40 d a purified diet whose lipid source (60 g/kg diet) was coconut, peanut, corn or fish (herring) oil. A low lipid (lipid-deficient) diet (corn oil, 2 g/kg diet) was also fed to some rats. There were no significant differences in final body weights of rats fed the coconut, peanut, and corn oil diets.

[Effects of several antilipemic agents on the activity of liver microsomal enzymes].

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.