Effect of Splenectomy on the Activity of Drug-Metabolizing Enzymes in the Liver of Rats

1971 ◽  
Vol 49 (3) ◽  
pp. 161-166 ◽  
Author(s):  
Jules Brodeur ◽  
Claude Marchand
Keyword(s):  
Indirect Evidence ◽  
Female Rats ◽  
Microsomal Enzymes ◽  
Drug Metabolizing Enzyme ◽  
Effect Of Splenectomy ◽  
Maximal Induction ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450 ◽  
Liver Microsomal Enzymes

Splenectomy was performed in adult female rats in order to investigate the influence of removal of the spleen on liver microsomal enzymes and cytochrome P-450 in vitro, as well as on the pharmacological activity of certain drugs in intact animals. Splenectomy significantly decreases the amount of cytochrome P-450 at 1 and 4 days after the operation, but not at 7 days. The activity of the enzymes catalyzing the metabolism of parathion, p-nitroanisole, and zoxazolamine is also decreased 4 days after splenectomy, whereas that of the enzymes involved in the metabolism of hexobarbital is unchanged. The maximal induction by phenobarbital of the enzymatic activities catalyzing the metabolism of parathion, p-nitroanisole, and zoxazolamine is prevented by splenectomy. Splenectomy exerts very little effect on plasma levels of hexobarbital and hexobarbital sleeping time; however, in both control and phenobarbital-pretreated rats, splenectomy results in a marked increase in the duration of zoxazolamine paralysis. These results indicate that splenectomy exerts inhibitory effects on certain liver microsomal enzymes, and provide some indirect evidence in support of the view that the hepatic blood supply is important for maintaining normal levels of drug-metabolizing enzyme activity in the liver.

scholarly journals Hepatic drug-metabolizing enzyme activity in rats pretreated with (−)-emetine or (±)-2,3-dehydroemetine

1970 ◽  
Vol 117 (3) ◽  
pp. 491-498 ◽  
Author(s):  
H. H. Miller ◽  
R. K. Johnson ◽  
J. D. Donahue ◽  
W. R. Jondorf
Keyword(s):  
Enzyme Activity ◽  
Female Rats ◽  
Inhibitory Effects ◽  
Hepatic Drug ◽  
Azo Reduction ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Sodium Phenobarbital ◽  
Stimulation Of

1. Pretreatment of female rats with (−)-emetine or (±)-2,3-dehydroemetine (at 18μmol/kg body wt. for 24h) prolongs the hexobarbital-induced sleeping-time of the treated animals. 2. This effect is not observed on pretreating animals with other compounds closely related to (−)-emetine, such as (−)-isoemetine or (+)-O-methylpsychotrine. 3. Liver microsomal drug-metabolizing enzyme activity in vitro as measured by N-demethylation of aminopyrine and azo-reduction of Neoprontosil is inhibited in rats pretreated with (−)-emetine or with (±)-2,3-dehydroemetine. 4. These inhibitory effects on drug metabolism in vitro are not observed in corresponding experiments involving pretreatment of rats with (−)-isoemetine or (+)-O-methylpsychotrine. 5. Co-administration of emetine or 2,3-dehydroemetine and sodium phenobarbital or 1,1-dichloro-2-o-chlorophenyl-2-p-chlorophenylethane to rats abolishes or greatly diminishes the stimulation of drug-metabolizing enzyme activity in vitro usually obtained by the administration of phenobarbital or 1,1-dichloro-2-o-chlorophenyl-2-p-chlorophenylethane alone. 6. Further, in rats pretreated with sodium phenobarbital and subsequently injected with emetine or 2,3-dehydroemetine the pre-stimulated drug-metabolizing enzyme activity in vitro is diminished. 7. The inhibitory effects on drug-metabolizing enzyme activity after pretreatment with (−)-emetine or (±)-2,3-dehydroemetine do not appear to be related to NADPH generation.

scholarly journals The role of cytochrome P-450 in cholesterol biogenesis and catabolism

1972 ◽  
Vol 128 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Sandra D. Atkin ◽  
Eileen D. Palmer ◽  
P. D. English ◽  
B. Morgan ◽  
M. A. Cawthorne ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Carbon Disulphide ◽  
Normal Serum ◽  
Liver Cholesterol ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cytochrome P 450

1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [14C]acetate or [14C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7α-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7α-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.

Actions of prednisolone acetate, pregnenolone-16α-carbonitrile, and triamcinolone upon drug resistance and metabolism: a comparative study

1977 ◽  
Vol 55 (3) ◽  
pp. 363-366 ◽  
Author(s):  
P. Kourounakis ◽  
H. Selye
Keyword(s):  
Plasma Concentrations ◽  
The Body ◽  
Female Rats ◽  
Prednisolone Acetate ◽  
Microsomal Enzyme ◽  
Enzyme Inducer ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Microsomal Enzyme Induction

In female rats, pretreatment with prednisolone acetate diminished the duration of zoxazolamine-induced paralysis as well as its plasma concentrations and increased significantly the in vitro metabolism of zoxazolamine and ethylmorphine. These actions of prednisolone were compared with those of equimolar amounts of pregnenolone-16α-carbonitrile (PCN) (a known microsomal enzyme inducer) and of triamcinolone (an agent that reduces the sensitivity of the body to drugs although not via microsomal enzyme induction). Prednisolone proved to be a strong drug-metabolizing enzyme inducer but it was less potent than PCN.

scholarly journals Generation of tetracycline-controllable CYP3A4-expressing Caco-2 cells by the piggyBac transposon system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moe Ichikawa ◽  
Hiroki Akamine ◽  
Michika Murata ◽  
Sumito Ito ◽  
Kazuo Takayama ◽  
...  
Keyword(s):  
Small Intestine ◽  
Drug Absorption ◽  
Cell Model ◽  
Negative Effects ◽  
Piggybac Transposon ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cyp3a4 Expression

AbstractCaco-2 cells are widely used as an in vitro intestinal epithelial cell model because they can form a monolayer and predict drug absorption with high accuracy. However, Caco-2 cells hardly express cytochrome P450 (CYP), a drug-metabolizing enzyme. It is known that CYP3A4 is the dominant drug-metabolizing enzyme in human small intestine. In this study, we generated CYP3A4-expressing Caco-2 (CYP3A4-Caco-2) cells and attempted to establish a model that can simultaneously evaluate drug absorption and metabolism. CYP3A4-Caco-2 cells were generated by piggyBac transposon vectors. A tetracycline-controllable CYP3A4 expression cassette (tet-on system) was stably transduced into Caco-2 cells, thus regulating the levels of CYP3A4 expression depending on the doxycycline concentration. The CYP3A4 expression levels in CYP3A4-Caco-2 cells cultured in the presence of doxycycline were similar to or higher than those of adult small intestine. The CYP3A4-Caco-2 cells had enough ability to metabolize midazolam, a substrate of CYP3A4. CYP3A4 overexpression had no negative effects on cell proliferation, barrier function, and P-glycoprotein activity in Caco-2 cells. Thus, we succeeded in establishing Caco-2 cells with CYP3A4 metabolizing activity comparable to in vivo human intestinal tissue. This cell line would be useful in pharmaceutical studies as a model that can simultaneously evaluate drug absorption and metabolism.

Inhibition of cytochrome P-450 C17 enzyme by a GnRH agonist in ovarian follicles from gonadotropin-stimulated rats

2007 ◽  
Vol 292 (5) ◽  
pp. E1456-E1464 ◽  
Author(s):  
Griselda Irusta ◽  
Fernanda Parborell ◽  
Marta Tesone
Keyword(s):  
Direct Action ◽  
Regulatory Protein ◽  
Follicular Development ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Serum Progesterone ◽  
Protein Levels ◽  
Androgen Synthesis ◽  
Cytochrome P 450

Our objective was to study the direct action of a GnRH-I agonist, leuprolide acetate (LA), on ovarian steroidogenesis in preovulatory follicles obtained from equine chorionic gonadotropin (eCG)-treated rats. Previously, we have demonstrated an inhibitory effect of LA on steroidogenesis and follicular development. In this study, we tested the hypothesis that gonadotropin-releasing hormone (GnRH) exerts its negative effect on follicular development by inhibiting thecal cytochrome P-450 C17 (P450C17) α-hydroxylase expression and, consequently, androgen synthesis. Studies were carried out in prepubertal female rats injected with either eCG (control) or eCG plus LA (LA) and killed at different time points. Immunohistochemical studies indicated that LA induced steroidogenic acute regulatory protein (StAR) expression mainly in theca cells of preantral and antral follicles. In addition, serum progesterone levels increased significantly ( P < 0.05), whereas those of androsterone decreased ( P < 0.05) after 8 h of LA treatment. This inhibition caused by LA seemed to be a consequence of the decreased expression of follicular P450C17 α-hydroxylase, as demonstrated by Western blot and RT-PCR techniques. In vitro studies using follicles isolated from 48-h-eCG-treated rats and cultured with LA showed a significant ( P < 0.05) inhibition of FSH-induced androsterone follicular content as well as P450C17 α-hydroxylase protein levels, as determined by Western analysis. However, LA increased StAR protein expression in these follicles without significant changes in P450scc enzyme levels. Taking all these findings into account, we suggest that GnRH-I exerts a direct inhibitory action on gonadotropin-induced follicular development by decreasing the temporal expression of the P450C17 enzyme and, consequently, androgen production, thus reducing the supply of estrogens available to developing follicles.

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