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T Cresteil

Publications and source records attributed to T Cresteil.

At least 73 records · Page 4Linked to original sources
PubMed1982

Pharmacological properties of dibenzo[a,c]cyclooctene derivatives isolated from Fructus Schizandrae chinensis. II. Induction of phenobarbital-like hepatic monooxygenases.

Schizandrin (Sin) A, B and C, Schizandrol (Sol) A and B and Schizandrer (Ser) A and B were isolated from Fructus Schizandrae chinensis, a traditional Chinese tonic. These components are the derivatives of dibenzo[a,c]cylooctene. Dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-biphenyl-2,2'-dicarboxylate (DDB) is an intermediate for synthesizing Sin C. The effect of these compounds on rat liver microsomal monooxygenases and epoxide hydrolase has been studied. Among these compounds, Sin B, Sin C, Sol B and DDB significantly increased rat liver cytochrome P-450 concentration, NADPH-cytochrome c reductase, benzphetamine and aminopyrene demethylase activities. The four compounds also markedly stimulated proliferation of smooth endoplasmic reticulum of liver cells. Metyrapone (1 mM) inhibited to a same extent (about 50%) the activity of aminopyrene demethylase of microsomes from rats treated by Sin B, Sin C, Sol B, DDB and phenobarbital (PB). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of liver microsomal preparations showed that Sin B and Sol B induce a major protein band of P-450 similar to that induced by PB. In addition, the effect of Sin B-, Sol B- and DDB-treated rat liver microsomes on [G-3H]-benzo[a]pyrene (BP) metabolism and covalent binding of reactive metabolites to DNA, in vitro, resembles that of PB. Dual induction of rats by Sol B and BP decreased mutagenicity of BP.

Animals↗
PubMed1982

Drug-metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P 450.

Cytochrome P 450 concentration, related monooxygenase activities (towards aniline, p-nitroanisole, benzphetamine, ethoxycoumarin, benzo(a)pyrene, testosterone, and dehydroepiandrosterone), epoxide hydrolase, and glutathione S-transferase activities were measured in the liver of human foetuses aged from 15 to 38 weeks and compared to adult activities. Different ontogenic patterns seem to exist between monooxygenase activities: if the overall cytochrome P 450 concentration, aniline hydroxylase, benzphetamine demethylase, epoxide hydrolase, and glutathione S-transferase activities reach about the half of adult values as early as 15-25 weeks of gestational age, the metabolism of benzo(a)pyrene, ethoxycoumarin, and testosterone in position 6 beta is very low in these foetuses, whereas the 16 alpha hydroxylation of dehydroandrosterone is higher than in adult human liver. Foetal and adult cytochromes P 450 were resolved by DEAE cellulose chromatography into three different fractions: in reconstitution experiments, the major fraction (A) was active toward aniline, whereas benzphetamine and ethoxycoumarin were mainly metabolized by the two other fractions (Ba and Bb). Results show that multiple cytochromes 450 are present in foetal liver and are able to catalyze, with a lower molecular activity, the same reactions as in adult human liver.

Aryl Hydrocarbon Hydroxylases↗
PubMed1981

Cytochrome P-450 monooxygenase activities in human and rat liver microsomes.

Microsomes were prepared from human livers obtained from renal donors of various ages and both sexes. Their drug-metabolizing capacity was measured and compared to that of rat liver microsomes. The following parameters were investigated: cytochrome P-450, cytochrome B5, NADPH-cytochrome c reductase, epoxide hydrolase, aryl hydrocarbon hydroxylase, benzphetamine N-demethylase, p-nitroanisole-O-demethylase, ethoxycoumarin-O-deethylase, steroid-16 alpha-hydroxylase. In addition, the metabolism of benzo(a)pyrene, progesterone, pregnenolone, testosterone, dehydroepiandrosterone and estradiol was studied in detail in vitro. The inhibitory effect of metyrapone and alpha-naphthoflavone on 7-ethoxycoumarin-O-deethylase was measured. The microsomal proteins of both species were separated by polyacrylamide gel electrophoresis in the presence of dodecyl sulfate. The following conclusions were drawn from the results obtained. Human liver microsomes can be stored under optimal conditions for the measurement of a large variety of enzymic activities. Human liver microsomes are able to metabolize the various xenobiotics used as substrates with a rate similar to that of female rat liver microsomes. No sex-linked difference in enzymic activity was observed in human microsomes. Significant differences in benzo(a)pyrene and steroid metabolism were registered when human and rat liver microsomes were compared. The monooxygenase activities, the sensitivity to in vitro alpha-naphthoflavone and metyrapone, the results of steroid metabolism, and slab gel electrophoresis are strong indications for multiplicity of human liver cytochrome P-450.

Animals↗
PubMed1981

Comparison of the effects of phenobarbital and its hydroxylated metabolites on drug-metabolizing enzymes during ontogenesis.

Twenty-two-day-old fetal and five-day-old newborn rats were pretreated with phenobarbital and its hydroxylated metabolites. Drug-metabolizing enzymes (cytochrome P450, epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione-S-transferase) and microsomal ribonuclease were not modified in fetuses treated with 80 or 400 mg . kg-1 of p-hydroxyphenobarbital, in spite of its accumulation in fetal liver. At fetal age, phenobarbital was a poor inducer of drug-metabolizing enzymes. In five-day-old newborns, p-hydroxyphenobarbital provoked a proliferation of endoplasmic reticulum without enzyme induction, whereas phenobarbital induced some drug-metabolizing enzymes. Thus, the effects of p-hydroxyphenobarbital and phenobarbital are retained in five-day-old rats, but undetectable in the fetuses.

Animals↗
PubMed1980

[Development of the mono-oxygenase system. Implications in perinatal pharmacotoxicology (author's transl)].

The hepatic or extra-hepatic mono-oxygenase activities ensure the metabolism of exogenic hydrophobic substances (xenobiotics) and endogenic substances (steroids). These substances easily cross the placenta ; it is of primary importance to know perfectly their possible transformation at the level of the foetus together with their excretion from the foetal compartment. We summarise here the data in the literature which describe the development of the mono-oxygenase system and the microsomal enzyme activities of phase II (epoxide hydrolase and UDP-glucuronosyl-transferase) both in the laboratory animal and in the human foetus. The influence of various factors (exogenic inducers, endogenic hormones) on the development of these activities is also reported. Although a conclusion is difficult concerning the present state of our knowledge, the main pharmacotoxicological consequences of the development of mono-oxygenasic activities are considered.

Adrenal Cortex Hormones↗
PubMed1979

Biotransformation of chloroform by rat and human liver microsomes; in vitro effect on some enzyme activities and mechanism of irreversible binding to macromolecules.

The effects of chloroform on some rat microsomal enzyme activities were studied in vitro. Maximum inhibition of oxygen consumption, NADPH oxidase and NADPH-cytochrome c reductase was observed at 0.5 mM chloroform; prior metabolization of CHCl3 by microsomal monooxygenases increased inhibition by about 50% at 0.2-0.5 mM chloroform. Higher concentrations produced a paradoxical reversal of inhibition, whereas p-nitroanisole demethylase was steadily inhibited by about 50% up to 10 mM chloroform. Irreversible binding of 14CHCl3 was confirmed to depend on chloroform metabolization by monooxygenases. The increased irreversible binding due to phenobarbital induction is accompanied by a diminished affinity towards chloroform as shown by increased KM of irreversible binding, and a higher spectral dissociation constant KS. Aminoacids with nucleophilic functions (histidine, cysteine) partially prevented the irreversible binding of chloroform metabolites to microsomes; non-volatile radioactive derivatives were recovered in trichloracetic acid supernatants when microsomes were incubated with cysteine, but not with histidine. Phosgene has been demonstrated as a biological metabolite of chloroform: its possible reactions with nucleophilic groups of macromolecules, water and added aminoacids partly explain these experimental data. Similar results were obtained with human microsomes, showing that chloroform hepatotoxicity in man could involve the same mechanisms.

Animals↗
PubMed1978

Formation of complexes between microsomal cytochrome P-450-Fe(II) and nitrosoarenes obtained by oxidation of arylhydroxylamines or reduction of nitroarenes in situ.

A cytochrome P-450 complex exhibiting a Soret peak at 454 nm is formed by direct interaction of nitrosobenzene with NADPH-reduced rat liver microsomes in anaerobic conditions, by reaction of phenylhydroxylamine with aerobic microsomes or during nitrobenzene reduction by NADPH-reduced or dithionite-reduced microsomes. In the latter conditions, the complex formation is only transient as it is unstable to dithionite. Analogous reactions with myoglobin lead to the previously described myoglobin-Fe(II)-nitrosobenzene complex which has similar properties to those of the 454-nm-absorbing cytochrome P-450 complex. This analogy, together with the various conditions of its formation, strongly indicates that it is a cytochrome-P-450-Fe(II)-nitrosobenzene complex. The corresponding complex with the 4-chloro-nitrosobenzene ligand is formed in similar conditions. Cytochrome P-450-Fe(II) complexes with nitrosoarenes seem less stable than the previously described complexes with nitrosoalkanes.

Animals↗
PubMed1977

Effect of the linoleic acid concentration of mother's diet on adenyl cyclase activity of fetal and neonatal rat brown adipose tissue.

An adenyl cyclase activity was measurable in the brown adipose tissue of fetal rat, and could be stimulated in vitro by noradrenaline during the last 3 days of fetal life. The stimulating effect of noradrenaline was maximal at birth and decreased during the first days of extrauterine life. Ingestion by mother of a high lipid diet modified the developmental pattern of fetal adenyl cyclase. The linoleic acid content of mother's diet had no effect on the noradrenaline- or fluoride-stimulated specific activities except on the day 22 of gestation. Relative noradrenaline-stimulated activity, expressed as a fraction of the maximal activity, was significantly increased in fetuses and 1-day-old newborns from mothers fed a high linoleic acid diet, but no effect was observed in suckling newborns.

Adenylyl Cyclases↗
PubMed1977

Noradrenaline appearance in guinea pig brown adipose tissue. Its significance in neonatal nonshivering thermogenesis.

A rapid growth of the guinea pig brown adipose tissue occurred during the last third of fetal life. Endogenous noradrenaline was measurable was measurable from day 55 of gestation and rose until birth. The maximal noradrenaline concentration was achieved on the first day of extrauterine life and remained constant during the postnatal period. So, noradrenaline was present in brown adipose tissue at birth and could mediate the neonatal nonshivering thermogenesis activation as suggested in the discussion.

Adipose Tissue↗
PubMed1977

Early postnatal metabolism of amino acids in rat.

The production of 14CO2 from glutamate and alanine studied in the newborn rat after injection of labeled precursors was intense and revealed an important catabolism from 130 nmol/hr in a 0-hr neonate to 2000 nmol/hr in 3-week-old rat. The degradative metabolism of leucine was low at birth (10 nmol/hr), but increased up to 500 nmol/hr in 3-week-old rat. Phenylalanine was practically not metabolized into CO2, but its incorporation into protein was higher than leucine, alanine, and glutamate incorporation. Glucose is the major fuel utilized by newborn rat for its energy supply (300-560 nmol/hr). However, the relative part of amino acids in energy production is important in the early neonate (0 and 1 hr after birth).

Alanine↗
PubMedDate not supplied

Specific and enantioselective sulfoxidation of an aryl-trifluoromethyl sulfide by rat liver cytochromes P-450.

Evidence based on thermal stability and enzyme inhibition data suggests that the sulfoxidation of the drug toltrazuril by rat liver microsomes is catalyzed by different cytochromes P-450. Pretreatment of rats by different inducers--phenobarbital, 3-methylcholanthrene, dexamethasone, and triacetyloleandomycin--results in a 2.1-, 2.6-, 2.9-, and 1.8-fold increase, respectively, in the rate of sulfoxidation. The highest increase (8.4-fold) was observed after treatment of microsomes from triacetyloleandomycin-treated animals by potassium ferricyanide. Castration and aging also modify the sulfoxidase activity. The relative rate of formation of the two toltrazuril enantiomers [(A)- and (B)-sulfoxides] depends on the source of the microsomes, suggesting that different cytochromes P-450 have different stereoselectivities.

Animals↗
PubMedDate not supplied

[Adenylate cyclase/Lipase. Hormone receptor induction].

An adenylate cyclase activity (AC) was found in guinea pig brown adipose tissue (BAT), since the tissue's apparition. This enzymatic activity increased during the development and showed high values at the end of gestation. An increase of AC units per cell was observed, in addition to the cell multiplication. A norepinephrine stimulation of AC activity was observed at the end of gestation : this regulating action disappeared in the first days of extrauterine life. Neither glucagon nor ACTH had any regulating role upon AC activity during fetal and newborn life. The basal lipolytic activity which was observed in BAT of fetuses (61rst day) and neonate dramatically around the 15th day. A potent lipolysis activation by norepinephrine was observed, but only after birth. The correlation observed between these enzymatic activities in presence of norepinephrine seems to indicate that the AC/lipase system was involved in the neonatal thermogenesis of guinea pigs.

Adenylyl Cyclases↗
PubMedDate not supplied

Effects of genetic or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin monooxygenase and cytochrome P-450-dependent monooxygenases.

Imipramine metabolism has been studied in both type I (streptozotocin-induced insulin-deficient) and type II (genetically insulin-resistant) diabetes in mice. In both types of diabetes, the formation of imipramine N-oxide is increased. In type I diabetes, desmethyl- and 2-hydroxyimipramine are additionally increased. The inhibition of imipramine metabolism by anti-cytochrome P-450 reductase antibodies led to the conclusion that cytochrome P-450-dependent monooxygenases are not involved in the N-oxidation of imipramine. This metabolic route is only supported by the flavin monooxygenase, whose activity is increased by diabetes. The pharmacological implications of altered imipramine metabolism in diabetic states are discussed in relation to the drug metabolism in human diabetes.

Animals↗