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PubMed1996

Cytochrome P4502E in vivo and in vitro in the dwarf goat: effects of enzyme induction and the applicability of chlorzoxazone as marker substrate.

Cytochrome P4502E activities, inducibility and the applicability of chlorzoxazone as a marker substrate for this enzyme were investigated in female dwarf goats. Goats were treated with either isoniazid or beta-naphthoflavone. Treatment with isoniazid resulted in a 1.4 fold increase of the chlorzoxazone hydroxylation rate in hepatic microsomes. Aniline- and p-nitrophenol hydroxylation rates were increased by roughly the same extent (1.6 and 1.25 fold resp.) and increased levels of cytochrome P4502E apoproteins were found by Western blotting. Treatment with the cytochrome P4501A inducer beta-naphthoflavone resulted in a 2.5 fold induction of the in vitro chlorzoxazone hydroxylation rate, whereas the hydroxylation rates of aniline and p-nitrophenol were not induced. After treatment with isoniazid, chlorzoxazone plasma clearance was increased from 5.0 mL/min/kg to 11.0 mL/min/kg. Chlorzoxazone was almost completely excreted in the urine as conjugated hydroxy metabolites. These results do not support the hypothesis that cytochrome P4502E is of particular importance in goats, as has been suggested earlier. Furthermore, chlorzoxazone has limited value as a marker substrate for this enzyme, since cytochrome P4501A enzymes appear to play an important role in its biotransformation.

Aniline Compounds↗
PubMed1990

Effect of liver denervation on compensatory changes in food intake, body composition and hepatic enzyme induction after food restriction in rats.

The mechanisms involved in the recovery of body fat and liver metabolism after food restriction and refeeding are not understood. This study's aim was to determine the need for hepatic neural input for the compensatory changes in food intake, body composition and hepatic lipogenic enzymes seen upon realimentation after energy restriction. Rats underwent total surgical hepatic denervation or had sham operations. One group of sham-operated and denervated rats was fed a semipurified diet ad libitum; a second group was restricted to 40% ad libitum levels for 7 d, then given free access to food during a 2-d refeeding period. Body fat content and body fat recovery rate from below "set point" were not altered by hepatic denervation. These observations do not rule out liver involvement because blood-borne factors communicating energy status information to the central nervous system could be released from the liver. The activities of hepatic enzymes--glucose-6-phosphate dehydrogenase, malic enzyme and citrate cleavage enzyme--were stimulated at least twofold by restriction and refeeding when compared to ad libitum feeding. Hepatic denervation had no effect on basal enzyme levels in ad libitum-fed animals or on elevated enzyme activity induced by refeeding after food restriction. This study clearly demonstrates that hepatic innervation is not essential for energy balance and body composition regulation. The induction of lipogenic enzymes by food restriction and refeeding does not depend on central nervous system input to the liver.

ATP Citrate (pro-S)-Lyase↗
PubMed1992

The profile of rat liver enzyme induction produced by prochloraz and its major metabolites.

1. The profile of the hepatic mixed-function oxidase system of male rats has been examined following treatment with prochloraz (I) and three of its major metabolites (II, III and IV). 2. The overall induction profile of prochloraz reflected the contribution of the individual metabolites. There was a slight increase of lauric acid hydroxylase, but by far the major induction was seen in the activity of aldrin epoxidase and 7-pentoxyresorufin-O-dealkylase (7- and 14-fold respectively). 3. N-Propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]urea (II), a primary intermediate in the metabolism of prochloraz, was a phenobarbitone-type inducer, increasing the activity of aldrin epoxidase and 7-pentoxyresorufin-O-dealkylase by 120% and 8-fold respectively. 4. The prochloraz metabolites, trichlorophenoxyethanol (III) and trichlorophenoxyacetic acid (IV) were both inducers of the clofibrate type, increasing the activity of lauric acid 12-hydroxylase. 5. The induction profile of prochloraz was of a mixed type, but the predominant characteristics were those of phenobarbitone induction.

Animals↗
PubMed1994

Hepatic enzyme induction potential of acitretin in male and female Sprague-Dawley rats.

Certain retinoids have been shown in rats and mice to induce the hepatic cytochrome P-450 enzyme system, and evidence from our laboratory suggested that acitretin, the active primary metabolite of etretinate (a retinoid used in the treatment of psoriasis) may induce its own metabolism. To test this hypothesis, male and female Sprague-Dawley rats were orally pretreated with acitretin for 18 days (10 mg/kg/day) and intravenously dosed with acitretin on day 20 (0.8-0.9 mg/kg). Serial blood samples were taken through 24 h, after which the hepatic microsomal proteins were harvested. Plasma concentrations of acitretin and its main metabolite isoacitretin were determined by HPLC, and total hepatic cytochrome P-450 concentrations and activities were determined using standard methods. Systemic clearance (17.4 +/- 2.5 and 12.1 +/- 1.6 mL/min per kg in control males and females, respectively), volume of distribution at steady state (Vss = 1568 +/- 353 and 1589 +/- 488 mL in control males and females, respectively), and mean residence time (MRT = 1.50 +/- 0.23 and 2.22 +/- 0.70 h in control males and females, respectively) were unchanged by acitretin pretreatment. Systemic clearance was 44% higher in control males than females. Concentrations of total microsomal protein (13.8 +/- 1.6 and 8.4 +/- 1.2 mg/g of liver in control males and females, respectively) and total P-450 (0.433 +/- 0.041 and 0.425 +/- 0.104 nmol/mg microsomal protein in control males and females, respectively) were also unchanged by acitretin pretreatment, as were microsomal levels of methoxy-, ethoxy-, pentoxy-, and (benzyloxy)resorufin O-dealkylation (MROD, EROD, PROD, and BROD, respectively) (control males and females, respectively, expressed as pmol of resorufin formed/min per mg of microsomal protein: MROD = 37.7 +/- 4.5 and 30.6 +/- 4.2; EROD 276 +/- 40 and 208 +/- 59; PROD = 15.2 +/- 4.5 and 5.8 +/- 1.2; and BROD 93.7 +/- 24.4 and 15.5 +/- 3.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗
PubMed1976

Impairment of enzyme induction by glucocorticoids in Zajdela hepatoma cells.

Whereas glucocorticoids induce TAT, TRP, GPT in liver and only TAT in HTC cells, no hormonal effect on the synthesis of these enzymes was found in Zajdela hepatoma cells grown in vivo as an ascitic tumor, or in vitro as layer cultures. Although these cells remain uninducible, the hormone penetrates normally, but a strong decrease of the specific binding of cytosol and nuclear proteins with the hormone was observed. The impairment at the level of the hormone receptors could account for the non-inducibility of enzyme synthesis in ZHC cells.

Alanine Transaminase↗
PubMed1997

A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers.

PURPOSE: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. METHODS: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of > or = 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-beta-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. RESULTS: VGB treatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/- 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 +/- 3.5 vs. 14.1 +/- 2.1 h), urinary 6-beta-hydroxycortisol excretion (488 +/- 164 vs. 470 +/- 228 nmol/ day), 6-beta-hydroxycortisol-to-cortisol concentration ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransferase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUC, 874 +/- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrel (half-life, 17.7 +/- 5.2 vs. 23.1 +/- 9.8 h; AUC, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 micrograms/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. CONCLUSIONS: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.

Adult↗