Glucocorticoid–dependent maintenance of CYP2C11–dependent oxidation in male rat liver in vivo

2000 ◽  
Vol 19 (2) ◽  
pp. 126-131 ◽  
Author(s):  
M Murray
Keyword(s):  
Rat Liver ◽  
Male Rats ◽  
Male Rat ◽  
Hormonal Factors ◽  
Adrenal Hormones ◽  
Male Specific ◽  
Physiological Correlate ◽  
Made In

1 Hormonal factors participate in the regulation of xenobiotic metabolising enzymes in liver. Hepatic xenobiotic oxidation capacity is decreased in adrena-lectomised rats, which directly implicates adrenal hormones in the control of cytochrome P450 (CYP) expression. In addition, recent studies in cultured hepatocytes have demonstrated that low concentra-tions of glucocorticoid upregulate the male-specific CYP2C11, which is a major enzyme that catalyses xenobiotic and steroid hydroxylations in rat liver. The present study evaluated whether glucocorticoid or mineralocorticoid may be the adrenal factor that contributes to the in vivo expression of CYP2C11 in liver. 2 Adrenalectomy of male rats selectively decreased CYP2C11-dependent 2a-/16a-hydroxylation of testos-terone and other steroid substrates to 60-70% of control, whereas activities mediated by other constitu-tive CYPs were unaffected. The decrease in CYP2C11 activity was due to impaired protein expression in liver after adrenalectomy. Administration of dexametha-sone (DEX; 0.2 mg/kg i.p. daily for 6 days) restored CYP2C11 activity and protein, whereas the mineralo-corticoid deoxycorticosterone (DOC) and adrenocorti-cotropic hormone (ACTH) were ineffective. 3 These findings establish that glucocorticoids have a partial role in the maintenance of CYP2C11 expression and associated microsomal oxidation in liver and provide a physiological correlate for similar observa-tions made in vitro in hepatocyte culture.

Quantification of the Uncertainties in Extrapolating From In Vitro Androgen Receptor Antagonism to In Vivo Hershberger Assay Endpoints and Adverse Reproductive Development in Male Rats

2020 ◽  
Vol 176 (2) ◽  
pp. 297-311
Author(s):  
Leon E Gray ◽  
Johnathan R Furr ◽  
Christy S Lambright ◽  
Nicola Evans ◽  
Phillip C Hartig ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Adverse Outcome ◽  
In Utero ◽  
Male Rats ◽  
Male Rat ◽  
Rat Offspring ◽  
Hershberger Assay ◽  
Key Events

Abstract Multiple molecular initiating events exist that disrupt male sexual differentiation in utero including androgen receptor (AR) antagonism and inhibition of synthesis, and metabolism of fetal testosterone. Disruption of androgen signaling by AR antagonists in utero reduces anogenital distance (AGD) and induces malformations in F1 male rat offspring. We are developing a quantitative network of adverse outcome pathways that includes multiple molecular initiating events and key events linking anti-AR activities to permanent reproductive abnormalities. Here, our objective was to determine how accurately the EC50s for AR antagonism in vitro or ED50s for reduced tissue growth in the Hershberger assay (HA) (key events in the adverse outcome pathway) predict the ED50s for reduced AGD in male rats exposed in utero to AR antagonists. This effort included in-house data and published studies from the last 60 years on AR antagonism in vitro and in vivo effects in the HA and on AGD after in utero exposure. In total, more than 250 studies were selected and included in the analysis with data from about 60 potentially antiandrogenic chemicals. The ability to predict ED50s for key events and adverse developmental effects from the in vitro EC50s displays considerable uncertainty with R2 values for HA and AGD of < 6%. In contrast, there is considerably less uncertainty in extrapolating from the ED50s in the HA to the ED50s for AGD (R2 value of about 85%). In summary, the current results suggest that the key events measured in the HA can be extrapolated with reasonable certainty to predict the ED50s for the adverse in utero effects of antiandrogenic chemicals on male rat offspring.

scholarly journals Metabolism of a glutathione conjugate of 2-hydroxyoestradiol by rat liver and kidney preparations in vitro

1970 ◽  
Vol 116 (5) ◽  
pp. 913-917 ◽  
Author(s):  
John S. Elce
Keyword(s):  
Rat Liver ◽  
Microsomal Fraction ◽  
Male Rat ◽  
Amino Group ◽  
Glutathione Conjugate ◽  
Acetyl Coenzyme A ◽  
Adult Male Rat ◽  
Liver And Kidney

Adult male rat liver and kidney preparations were incubated with (2-hydroxyoestradiol-1-yl)[35S]glutathione. The glutamic acid and glycine residues were removed by enzymes present in the kidney microsomal fraction; the liver preparations had no effect. The resulting 2-hydroxyoestradiol–cysteine conjugate was acetylated at the α-amino group by both liver and kidney homogenates fortified with acetyl-coenzyme A, but not significantly in the absence of this coenzyme, or by liver or kidney slices. These results suggest that an oestrogen–glutathione conjugate, if formed in vivo, would be converted into the corresponding mercapturic acid before excretion.

THE EFFECT OF 2-BROMO-α-ERGOCRYPTINE (CB154) ADMINISTRATION ON THE HORMONE LEVELS, ORGAN WEIGHTS, PROSTATIC MORPHOLOGY AND ZINC CONCENTRATIONS IN THE MALE RAT

1976 ◽  
Vol 83 (1) ◽  
pp. 211-224 ◽  
Author(s):  
M. E. Harper ◽  
V. Danutra ◽  
J. A. Chandler ◽  
K. Griffiths
Keyword(s):  
Prostatic Tissue ◽  
Male Rats ◽  
Male Rat ◽  
Plasma Prolactin ◽  
Cell Organelles ◽  
Adenyl Cyclase Activity ◽  
Zinc Concentrations ◽  
High Concentrations

ABSTRACT 2-Bromo-α-ergocryptine (CB154) administration to male rats produced a significant decrease in plasma prolactin levels without changing the LH and testosterone concentrations. The weights of the accessory sex tissues, testes, adrenals and kidney were unaltered by the treatment. Zinc concentration and distribution in the cell organelles of the prostatic tissue was markedly changed by CB154 treatment. No changes in the uptake of testosterone in vivo occurred in the treated animals. Prolactin did not consistently influence the prostatic adenyl cyclase activity in vitro and only at high concentrations was the testosterone uptake in vitro with cultures of prostatic tissue increased.

scholarly journals Metabolism and Tissue Distribution of Chelerythrine and Effects of Macleaya Cordata Extracts on Liver NAD(P)H Quinone Oxidoreductase

2021 ◽  
Vol 8 ◽  
Author(s):  
Chong-Yin Huang ◽  
Ya-Jun Huang ◽  
Zhuo-Yi Zhang ◽  
Yi-Song Liu ◽  
Zhao-Ying Liu
Keyword(s):  
Tissue Distribution ◽  
Rat Liver ◽  
Metabolic Pathway ◽  
Male Rats ◽  
Intragastric Administration ◽  
Main Metabolic Pathway ◽  
Macleaya Cordata ◽  
The Impact

Background:Macleaya cordata (Willd.) (Papaveraceae) is listed as a feed additive in animal production by the European Food Authority.Methods: The metabolites of chelerythrine in rats were measured in vitro and in vivo by rapid and accurate high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). The structures of CHE metabolites were elucidated by comparing their changes in accurate molecular masses and fragment ions with those of parent ion or metabolite. The metabolic enzymes that were involved in chelerythrine reduction were investigated using an inhibition method. The tissue distribution of chelerythrine and the effects on NQO1 following intragastric administration with M. cordata extracts in rats were examined.Results: A total of twelve metabolites of chelerythrine were characterized by this approach in rat liver S9 and in vivo. The reduction of the iminium bond of chelerythrine and subsequent O-demethylation was the main metabolic pathway of chelerythrine in rat liver S9 while the reduction of the iminium bond of chelerythrine was the main metabolic pathway of chelerythrine in rats in vivo. After the rats were given intragastric administration, the low concentration residues of sanguinarine and chelerythrine in different rat tissues were found at 48 h after the last dose, suggesting that both compounds could be widely distributed in tissues. The results also indicated that XO, NQO1, NQO2, and carbonyl reductase are involved in chelerythrine reduction. Macleaya cordata extracts treated female and male rats, respectively, showed different responses, inhibiting NQO1 activity in males, but inducing NQO1 activity in females. Chelerythrine had a weak impact on NQO1 activity, but sanguinarine inhibited NQO1 activityConclusion: Through studying the effects of cytosolic reductase inhibitors on chelerythrine reduction and the impact of chelerythrine and sanguinarine on the activity of NQO1 in vitro and in vivo, we clarified the potential drug interaction of Macleaya cordata extract in clinical application, so as to provide theoretical guidance for clinically safe medication. In addition, it provided a reference basis for the metabolic mechanism of chelerythrinein rats.

PRODUCTION OF MALE PSEUDOHERMAPHRODITISM IN RATS BY TWO NEW INHIBITORS OF STEROID 17α-HYDROXYLASE AND C 17-20 LYASE

1976 ◽  
Vol 71 (3) ◽  
pp. 289-297 ◽  
Author(s):  
A. S. GOLDMAN ◽  
R. D. EAVEY ◽  
MARY K. BAKER
Keyword(s):  
Enzyme Inhibitors ◽  
Neonatal Rat ◽  
Male Rats ◽  
Male Rat ◽  
Pregnant Rats ◽  
Adult Rat ◽  
Rat Pups ◽  
Potent Inhibition

SUMMARY Two new synthetic steroid analogues, (I) 16β-bromo-3β,17α-dihydroxy-5α-pregnane-11,20-dione and (II) 17β-ureido-1,4-androstadien-3-one have been shown to give kinetic patterns consistent with active-site-directed irreversible inhibition of adult rat testicular microsomal steroid 17α-hydroxylase and C17-20 lyase in vitro. Administration of both analogues to adult male rats for 24 h produced potent inhibition of these testicular enzymes in vivo. Given to pregnant rats during the critical period of male organogenesis they produced hypospadias: a characteristic of the syndrome in man in which these enzymes are defective genetically. Given to male rat pups during the first 9 days of life, inhibitor II produced significantly smaller prostates and seminal vesicles in adulthood, indicating the usefulness of this inhibitor in studies on the role of testosterone in neonatal programming of target organ size in adulthood. Thus, two new enzyme inhibitors have been shown to block testosterone production in the foetal and neonatal rat selectively at the site of the hydroxylase without other apparent hormonal effects or influence on adrenal size.

scholarly journals Features of hemostatic activity of 2-[3-methyl-1-h-propyl-7-(1,1-dioxothiethanyl-3) xantinyl-8-thio] acetic acid cyclohexilammonium salt

2013 ◽  
Vol 94 (4) ◽  
pp. 549-552
Author(s):  
F Kh Kamilov ◽  
G A Timirkhanova ◽  
A I Samorodova ◽  
F A Khaliullin ◽  
R A Gubaeva
Keyword(s):  
Acetic Acid ◽  
Male Rats ◽  
Control Group ◽  
Hemostatic Activity ◽  
Platelet Aggregates ◽  
Aggregation Parameters ◽  
Average Size ◽  
Made In

Aim. To study the systemic hemostatic activity of firstly synthesized 2-[3-methyl-1-h-propyl-7-(1,1-dioxotiethanyl-3) xantinyl-8-thio] acetic acid cyclohexilammonium salt in vitro and in vivo. Methods. Experiments in vitro using the blood samples form healthy male donors, and in vivo on male rats by intraperitoneal injection of the equimolar concentrations of researched substances. The effect of the firstly synthesized xantine and etamsylate derivative on the platelet functional activity in vitro and in vivo was studied using a platelet aggregation laser analyzer «Biola 230 LA» (Russia). 20 mkg/ml of adenosinediphosphate and 5 mg/ml of collagen (produced by «Technologia-Standart» company, Russia) were used as an aggregation inducers. Aggregation was analyzed using the AGGR software. General aggregation parameters, maximal aggregation value, maximal aggregation speed, average size of platelet aggregates were analyzed. Experimental assessment of specific systemic hemostatic activity in vivo was made in accordance with the parenchymal hemorrhage model on mature male rats. Coagulation time and blood loss volume were registered. Results. 2-[3-Methyl-1-h-propyl-7-(1,1-dioxotiethanyl-3) xantinyl-8-thio] acetic acid cyclohexilammonium salt showed a pro-aggregative effect both in vitro and in vivo. 2-[3-Methyl-1-h-propyl-7-(1,1-dioxotiethanyl-3) xantinyl-8-thio] acetic acid cyclohexilammonium salt pro-aggregative effect which was observed both in vitro and in vivo increased the systemic hemostatic activity, exceeding the results of the control group and etamsylate group. Conclusion. The findings reveal potentially high systemic hemostatic activity of 2-[3-methyl-1-h-propyl-7-(1,1-dioxotiethanyl-3) xantinyl-8-thio] acetic acid cyclohexilammonium salt and confirm the need for further studies of this compound and its equivalents in order to create highly effective selective hemostasis correctors on their basis.

Effects of acute hepatic ischemia on the electrophoretic patterns of the polypeptides and phosphopolypeptides of the microsomal membrane fraction of rat liver

1980 ◽  
Vol 58 (10) ◽  
pp. 1039-1050 ◽  
Author(s):  
Monique Behar-Bannelier ◽  
Les Pinteric ◽  
Robert K. Murray
Keyword(s):  
Rat Liver ◽  
Membrane Fraction ◽  
Sodium Dodecyl ◽  
Microsomal Membrane ◽  
Male Rats ◽  
Base Line ◽  
Hepatic Ischemia ◽  
Electrophoretic Patterns

The purpose of this study was to establish when alterations of the electrophoretic patterns of the polypeptides and phosphopolypeptides of the microsomal membrane fraction of the livers of rats become observable after initiation of acute hepatic ischemia. Ischemia was initiated by clamping the vascular supply to the left and median lobes of the livers of adult male rats. The animals were killed at various times thereafter (up to 6 h, and in certain instances, 24 h) and microsomal membrane fractions were prepared from each. The patterns of the polypeptides and phosphopolypeptides of these fractions were analysed by sodium dodecyl sulfate – polyacrylamide gel electrophoresis, using staining with Coomassie blue to analyse the polypeptides and radioautography to analyse 32P-labelled phosphopolypeptides. Alterations of the polypeptide pattern were apparent in the fractions from animals killed at 4 h and after; prior to this time point, subtle alterations, at most, could be distinguished. Effects of acute ischemia on the pattern of phosphopolypeptides of the microsomal membrane fraction were studied after phosphorylation in vivo (produced by intraperitoneal injection of [32P]phosphoric acid) and in vitro (using [γ-32P]ATP as phosphate donor). No marked changes in the phosphopolypeptide pattern produced by phosphorylation in vivo were observed until 6 h after clamping, by which time a diminution of the radioactivity in the majority of the phosphopolypeptides was evident. However, noteworthy alterations of the pattern of phosphopolypeptides produced by phosphorylation in vitro were observable in the membrane fractions from animals subjected to 2 h of ischemia. Overall the study provides a base line delineating the time sequence during which alterations of the electrophoretic patterns of the polypeptides and phosphopolypeptides of rat liver microsomal membranes become evident following the onset of acute hepatic ischemia and reveals that gross alterations of the polypeptide patterns of these membranes and of certain other subcellular fractions are not an early occurrence following this severe type of injury. The possible utility of the application of phosphorylation in vitro for detecting early alterations in membrane structure following cell injury is suggested.

FURTHER STUDIES ON THE UPTAKE OF ANDROGEN BY SOME ORGANS OF THE MALE RAT

1970 ◽  
Vol 63 (3) ◽  
pp. 489-498 ◽  
Author(s):  
Kjell J. Tveter
Keyword(s):  
Muscle Tissue ◽  
Specific Activity ◽  
Seminal Vesicles ◽  
Radioactive Material ◽  
Male Rats ◽  
Ventral Prostate ◽  
Supernatant Fraction ◽  
Male Rat

ABSTRACT [1,2-3H]Testosterone with a specific activity of 42.3 Ci/mmole was injected intramuscularly to adult castrated male rats. There was a selective uptake of radioactivity by the prostate, where a high and prolonged accumulation of radioactive material was found, in contrast to the much lower uptake by muscle tissue. The influence of castration on the uptake was investigated. In the ventral prostate, the uptake was 205% higher in animals castrated 24 h previously than in non-castrated animals. The corresponding values for the lateral prostate, the coagulating glands and the seminal vesicles were 120%, 165% and 213% respectively. The uptake by the dorsal prostate was only about 23% higher one day after orchidectomy. The uptake by muscle was apparently not influenced by castration. Following homogenization of the coagulating glands and the dorsal and ventral prostate, some of the radioactivity in the 105 000 × g supernatant fraction 1 h after the administration of [1,2-3H] testosterone in vivo was associated with macromolecules. In the lateral prostate an interaction between radioactive material and soluble macromolecules was only found in vitro.

The interrelationships of thyroid and growth hormones: effect of growth hormone releasing hormone in hypo- and hyperthyroid male rats

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S367-S375 ◽  
Author(s):  
Allen W. ROOT ◽  
Dorothy SHULMAN ◽  
Jennifer ROOT ◽  
Frank DIAMOND
Keyword(s):  
Growth Hormone ◽  
Thyroid Hormones ◽  
Secretory Response ◽  
Metabolic Effects ◽  
Male Rats ◽  
Male Rat ◽  
Peripheral Tissues ◽  
Releasing Hormone

ABSTRACT Growth hormone (GH) and the thyroid hormones interact in the hypothalamus, pituitary and peripheral tissues. Thyroid hormone exerts a permissive effect upon the anabolic and metabolic effects of GH, and increases pituitary synthesis of this protein hormone. GH depresses the secretion of thyrotropin and the thyroid hormones and increases the peripheral conversion of thyroxine to triiodothyronine. In the adult male rat experimental hypothyroidism produced by ingestion of propylthiouracil depresses the GH secretory response to GH-releasing hormone in vivo and in vitro, reflecting the lowered pituitary stores of GH in the hypothyroid state. Short term administration of large amounts of thyroxine with induction of the hyperthyroid state does not affect the in vivo GH secretory response to GH-releasing hormone in this animal.

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