Liver Microsomal Cytochrome P-450 Content Research Articles

Comparative effects of dexamethasone and phenobarbital on adrenal cortex, liver cytochrome P450 contents and serum thyroid hormones

The effects of dexamethasone and phenobarbital on adrenocortical mitochondria and microsomes, and on liver microsomes were investigated in the rat. Dexamethasone injection (300 μg/100g s.c. twice a day for 2 days) increased by 32% liver wt. and decreased by 14% adrenal wt. Cytochrome P450 contents, both in liver microsomes and in adrenal cortex mitochondria and microsomes, were decreased by about 20 to 25%. Phenobarbital treatment (5mg/100g i.p. twice a day for 2 days) increased both liver and adrenal wt. by 26 and 35% respectively. It induced an increase in liver microsomal cytochrome P450 content, but no change was observed in adrenal cortex mitochondria and microsomes. The effects of dexamethasone and phenobarbital on deioclinating systems located in liver microsomes were indirectly studied by the estimation of serum concentrations of 3,5,3'-triiodo- l-thyronine (T 3), l-thyroxine (T 4) and 3,3',5'-triiodo- l-thyronine (rT 3). Dexamethasone administration slightly diminished T 4 concentration and increased rT 3 concentration without a correlative decrease of T 3 in serum. Phenobarbital decreased T 4 and T 3 serum concentration however rT 3 was unchanged.

Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (gluatmic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver gluatthione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 19% and hepatic demethylation of aminopyrine by 46%. it afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thiocetamied, but did not influence the antiphlogistic activity of paracetamol (carrageebab paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subcutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate that the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cuase of the paracetamol-induced protection against paracetamol hepatotoxicity.

Starvation and phenobarbital treatment effects on drug hydroxylation and glucuronidation in the rat liver and small intestinal mucosa

Drug hydroxylation and glucuronidation enzyme levels were measured in the liver and small intestinal mucosa of male rats after starvation for 3 days and after starvation combined with phenobarbital treatment (80 mg/kg, 3 days). After simple starvation liver microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were unaffected, while p-nitroanisole demethylase activity was increased. Specific activities of the UDPglucose dehydrogenase, total β-glucuronidase and 3-hydroxy-acid dehydrogenase were increased, UDPglucuronosyltransferase was unaffected and glucuronolactone dehydrogenase was decreased. When activities were calculated per whole liver, all enzymes tested were decreased during starvation due to the reduction of the liver weight. In the small intestinal mucosa specific enzyme activities were lower in the starved animals, with the exception of UDPglucuronosyl-transferase which was not changed. The excretion into the urine of d-glucaric and l-ascorbic acid, two final products of the glucuronic acid pathway in the rat, was decreased by fasting. Phenobarbital treatment proved more effective in inducing several enzymes in the starved animals than in those fed ad lib. This compensated for the reduction of total activities due to the loss of liver weight. Despite fasting, the excretion into the urine of d-glucaric and l-ascorbic acid was enhanced after treatment with phenobarbital, and d-glucaric acid reached the levels found in normally fed rats. These findings suggest that starvation impairs drug-metabolism in the rat liver and small intestinal mucosa. Inducibility of the drug-metabolizing enzymes, however, is not depressed by this condition, but on the contrary it is markedly enhanced.

Selection of inducers: An important factor in characterizing genetic differences to induction of aryl hydrocarbon hydroxylase in strains of mice

The effect of various microsomal enzyme inducers such as DDT, benzpyrene, 3-MC, TCDD or phenobarbital on liver microsomal mixed-function oxidases and cytochrome P450 content in mice genetically responsive (C57B1/6J) and resistant (DBA/2J) to induction of aryl hydrocarbon hydroxylase (AHH) was studied. 3-MC and benzpyrene administration stimulated liver AHH activity 6–8 fold in C57B1/6J mice but had no effect in DBA/2J mice. However, intraperitoneal administration of TCDD increased AHH activity in both C57BL/6J and DBA/2J mice. This increase was accompanied by shift in the peak of cytochrome P450 difference spectrum from 450 to 448 nm. It is concluded that genetic resistance to AHH stimulation in DBA/2J mice is influenced by the type of inducer used.