28 research outputs found
Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17-Estradiol-3-benzoate
ABSTRACT Tamoxifen, a nonsteroidal antiestrogen, is used widely in the treatment of breast cancer and is undergoing evaluation as a chemopreventive agent. In this study, we investigated several long-term effects of tamoxifen in intact adult female rats following acute treatment at various dosages. The effects of tamoxifen on somatic growth, growth hormone (GH) levels, thyroid hormone levels, and on hepatic cytochrome P450 (P450) expression were compared with those of fulvestrant (ICI 182,780), 17-estradiol-3-benzoate, and 4-hydroxytamoxifen under the same experimental conditions. Each compound was injected s.c. for two consecutive days, and rats were killed 37 days after treatment. Tamoxifen decreased body weight and serum triiodothyronine (T3) levels at dosages ranging from 0.5 to 200 mg/kg. Ovary weight, uterus weight, peak plasma GH concentration, and hepatic CYP2A1 content were decreased 37 days after treatment with tamoxifen at a dosage of 20 mg/kg, but expression of other P450 enzymes was not affected. However, tamoxifen and 4-hydroxytamoxifen could not be detected in plasma by high performance liquid chromatography analysis at this time, which suggests that the effects of tamoxifen were mediated indirectly. 4-Hydroxytamoxifen exhibited effects similar to those of tamoxifen, indicating that this metabolite contributes to the in vivo activity of tamoxifen. Estradiol benzoate decreased CYP2A1 and increased CYP3A hepatic levels, but had no effect on serum T3 concentration. In contrast, treatment with ICI 182,780 had little or no effect on the endpoints measured. In summary, 2-day tamoxifen treatment of intact adult female rats resulted in persistent suppression of somatic growth, serum T3 levels, and hepatic CYP2A1 expression
Effects of Norepinephrine and Acetylcholine on the Development of Cultured Leydig Cells in Mice
Few data have suggested how norepinephrine (NE) and acetylcholine (Ach) regulate the development of Leydig cells in mice at prepuberty, except for data indicating endocrine effects. The present study aims to elucidate the roles of NE and Ach on the differentiation and proliferation of Leydig cells. Firstly, the expression of adrenergic receptors and muscarinic acetylcholine receptors in Leydig cells was investigated. It was found that adrenergic receptors (β1AR, β2AR, and α1D) and muscarinic acetylcholine receptors (M1 and M3) mRNA are expressed in adult Leydig cells. Then, the effects of NE and Ach on the differentiation and proliferation of Leydig cells were analyzed. The results showed that NE and Ach at 10 μM significantly increased the number of 3β-hydroxysteroid-dehydrogenase-(3β-HSD-) positive Leydig cells and improved the expression of proliferating cell nuclear antigen (PCNA) in Leydig cells on postnatal day (PD) 15 (P < 0.05). NE and Ach at 10 μM had no impact on the expression of PCNA mRNA (P > 0.05), but reduced the expression of 3β-HSD mRNA in adult Leydig cells and a murine Leydig tumor cell line (MLTC-1) (P < 0.05). Therefore, a conclusion may be reached that NE and Ach participated in stimulating the development of Leydig cells in mice from prepuberty to adult stage
MODULATION OF HEPATIC CYP2A1, CYP2C11, AND CYP3A9 EXPRESSION IN ADULT RATS BY NEONATAL ADMINISTRATION OF TAMOXIFEN
This paper is available online at http://www.dmd.org ABSTRACT: To examine the effect of neonatal administration of tamoxifen on adult expression of hepatic cytochrome P-450 (CYP) enzymes and steroid 5␣-reductase, male and female Sprague-Dawley rats were injected s.c. with tamoxifen (20 g) or peanut oil (control) once daily at days 1 to 5 of age and sacrificed at 3 months of age. Neonatal tamoxifen treatment did not affect b.wt. or liver weight of adult male and female rats, but decreased testicular weight by approximately 40% in adult male rats. Neonatal administration of tamoxifen decreased hepatic microsomal testosterone 6-and 7␣-hydroxylase activities in adult female rats whereas it did not alter steroid 5␣-reductase activity. The same treatment increased testosterone 7␣-hydroxylase activity, but did not affect testosterone 6-hydroxylase or steroid 5␣-reductase activity in adult male rats. Immunoblot analysis indicated that neonatal tamoxifen treatment decreased CYP2C11 protein level by 26% and increased CYP2A1 protein content by 2.6-fold in adult male rats, whereas it had no effect on CYP3A or CYP2B protein expression. The reduction in the CYP3A-mediated testosterone 6-hydroxylase activity in adult female rats was accompanied by a decrease in CYP3A9 mRNA expression. Analysis of serum hormone levels indicated that neonatal exposure to tamoxifen resulted in a decrease in serum 17-estradiol concentration in adult female rats, whereas it did not alter serum testosterone concentration in adult male rats. In summary, treatment of neonatal rats with tamoxifen produced a longlasting effect on hepatic CYP2A1, CYP2C11, and CYP3A9 expression in addition to testicular weight and serum 17-estradiol concentration
Evaluating toxic endpoints of exposure to a commercial PCB mixture: an in vivo laboratory study
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that produce a wide range of toxic effects. To determine sensitive endpoints in various organ systems, the effects of Aroclor 1260 on immune, endocrine, and hepatic systems were evaluated in a dose-response study. Nine-week old male rats were treated with Aroclor 1260 by oral gavage at dosages ranging from 0.025 to 156 mg/kg/day for 10 consecutive days and killed two days after the last treatment. Eight days prior to sacrifice, rats were injected i.v. with sheep red blood cells (SRBC) for determination of humoral immunity. No observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL) were determined for liver, thymus and genital organ weights, body weight, serum luteinizing hormone (LH), testosterone, thyroxine and thyroid-stimulating hormone (TSH) concentrations, hepatic microsomal testosterone hydroxylase activities, and hepatic microsomal cytochrome P450 (CYP) 1A1, CYP1A2, CYP2B1 and CYP2B2 protein levels. Treatment with Aroclor 1260, at all dosages, had no effect on testis, seminal vesicle or ventral prostate weights, on thymus weight or on serum LH or testosterone levels. Among the endpoints altered by Aroclor 1260, the most sensitive, with a LOAEL of 1.25 mg/kg/day, were increased testosterone 16β-hydroxylase activity and androstenedione formation. The LOAEL for increased liver weight, testosterone 16α-hydroxylase activity and CYP2B1 protein content was 3.13 mg/kg/day, while the LOAEL for decreased serum thyroxine levels and anti-SRBC IgM titer was 6.25 mg/kg/day. Less sensitive responses, as reflected by larger LOAEL values, included CYP1A enzyme induction and decreased body weight. In summary, comparison of NOAEL and LOAEL values indicated that hepatic CYP2B-mediated activities were a more sensitive response to Aroclor 1260 exposure in male rats than immune or endocrine endpoints
Identification of Human Hepatic Cytochrome P450 Enzymes Involved in the Biotransformation of Cholic and Chenodeoxycholic Acid
3-Ketocholanoic Acid Is the Major in Vitro Human Hepatic Microsomal Metabolite of Lithocholic Acid
Biotransformation of Lithocholic Acid by Rat Hepatic Microsomes: Metabolite Analysis by Liquid Chromatography/Mass Spectrometry
Regioselective versatility of monooxygenase reactions catalyzed by CYP2B6 and CYP3A4 : examples with single substrates
Evaluation of hepatic biotransformation of polybrominated diphenyl ethers in the polar bear (Ursus maritimus)
Polar bears are at the top of the Arctic marine food chain and are subject to exposure and bioaccumulation of environmental chemicals of concern such as polybrominated diphenyl ethers (PBDEs), which were widely used as flame-retardants. The aim of the present study was to evaluate the in vitro oxidative metabolism of 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) and 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) by polar bear liver microsomes. The identification and quantification of the hydroxy-brominated diphenyl ethers formed were assessed using an ultra-high performance liquid chromatography-tandem mass spectrometry-based method. Incubation of BDE-47 with archived individual liver microsomes, prepared from fifteen polar bears from northern Canada, produced a total of eleven hydroxylated metabolites, eight of which were identified using authentic standards. The major metabolites were 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether and 5′-hydroxy-2,2'4,4'-tetrabromodiphenyl ether. Incubation of BDE-99 with polar bear liver microsomes produced a total of eleven hydroxylated metabolites, seven of which were identified using authentic standards. The major metabolites were 2,4,5-tribromophenol and 4-hydroxy-2,2′,3,4′,5-pentabromodiphenyl ether. Among the CYP specific antibodies tested, anti-rat CYP2B was found to be the most active in inhibiting the formation of hydroxylated metabolites of both BDE-47 and BDE-99, indicating that CYP2B was the major CYP enzyme involved in the oxidative biotransformation of these two congeners. Our study shows that polar bears are capable of forming multiple hydroxylated metabolites of BDE-47 and BDE-99 in vitro and demonstrates the role of CYP2B in the biotransformation and possibly in the toxicity of BDE-47 and BDE-99 in polar bears.Medicine, Faculty ofPharmaceutical Sciences, Faculty ofReviewedFacultyUndergraduateUnknow