摘要:

AbstractHexachlorobenzene (HCB) is a persistent environmental contaminant which has been measured in human serum, fat, semen, and follicular fluid. In animal testing HCB has been shown to be a reproductive toxin. Discrepant results were obtained from prior studies concerning the effect of HCB treatment on ovarian steroidogenesis. The current study was designed to assess the impact of HCB on the ovary and gonadal steroid levels in the superovulated rat. Female Sprague‐Dawley rats (n= 24) were dosed with HCB (0.0, 1.0, 10.0, or 100.0 mg/kg BW/day) for 21 days. All rats received 10 IU pregnant mare serum gonadotropin (PMSG) s.c. on day 18 of treatment and 15 IU of human chorionic gonadotropin (hCG) on day 20. A terminal blood sample was collected and circulating levels of estradiol (Emr2) and progesterone. (P4) were determined. Serum concentrations of P4were significantly (p<0.0034) elevated by HCB treatment at all dose levels. Ovarian weights were significantly increased (p<0.05) in the lowest dose group only compared to the control group. Serum concentrations of Evuterine weight, weight gain, and general animal health were not affected by HCB treatment. We conclude that during HCB treatment the rat ovary remains responsive to gonadotropin stimulation. Moreover, it is suggested that HCB effects on ovarian steroidogenesis are indirec

ISSN:0887-2082    

DOI:10.1002/jbt.2570070102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractIn the present study we report the in vivo interaction of acrylonitrile (VCN) with testicular tissue in rats. Covalent binding of radioactivity to testicular tissue DNA was examined for a period of 72 hr after a single oral dose (46.5 mg/kg) of [2, 3‐14C] VCN. Maximal covalent binding was observed at 0.5 hr (8.9 μmol VCN equivalent/mol nucleotide). Binding decreased gradually thereafter but was still detected (2.5 μmol VCN equivalent/mol nucleotide) at 72 hr following VCN administration. Further, we examined the effects of VCN on DNA synthesis and repair in the testes of rats following a single oral dose (46.5 mg/kg) of VCN to clarify the impact of the covalent binding observed on the testicular genetic material. A significant decrease in DNA synthesis (80% of control) was observed at 0.5 hr after treatment. At 24 hr following acrylonitrile administration, testicular DNA synthesis was severely inhibited (38% of control). Testicular DNA repair was increased 1.5‐fold at 0.5 hr and more than 3.3‐fold at 24 hr following treatment with VCN. These results suggest that VCN can act as a multipotent genotoxic agent by alkylating DNA in testicular tissue and may affect the male reproductive function by interfering with testicular DNA synthesis and repair pr

ISSN:0887-2082    

DOI:10.1002/jbt.2570070103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractTreatment of isolated rat liver nuclei with 7β, 8α‐dihydroxy‐9α, 10α‐epoxy‐7, 8, 9, 10‐tetrahy‐drobenzo[a]pyrene, the ultimate carcinogenic metabolite of benzo[a]pyrene, resulted in inhibition of transcription as measured by radioactive precursor incorporation into RNA. The mechanism of inhibition as analyzed by use of different types of inhibitors suggested that the carcinogen acted on both the major components of transcription machinery, that is, the template chromatin and the enzyme RNA polymerases. This action correlates well with the observations made after administration of benzo[a

ISSN:0887-2082    

DOI:10.1002/jbt.2570070104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAdministration of the carcinogenic N‐nitroso compound,N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in drinking water (0.5 mg/mL) to male Wistar rats for 1 week caused impairment of in vivo and in vitro incorporation of [14C]leucine into stomach mucosal protein. This impairment gradually returned to normal after 4 weeks. Uptake of [14C]leucine into mucosal protein was significantly inhibited after in vitro treatment of stomach mucosa with the carcinogen. Addition of theN‐nitroso compound in a cell‐free system using postmitochondrial supernatant prepared from stomach mucosa also showed inhibition of amino acid incorporation. Using a more defined system consisting of purified polyribosome from stomach mucosa and pH 5 enzyme fraction derived from liver it was further demonstrated that the carcinogen purturbed protein synthesizing ability of polyribosome, under both in vivo and in vitro treatment conditions. In these respects this carcinogen has similar action on the target tissue of stomach as in the liver, although the in vivo effect may be related more to toxicity tha

ISSN:0887-2082    

DOI:10.1002/jbt.2570070105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractPerfluorodecanoic (PFDA) and perfluorooctanoic (PFOA) acids belong to the structurally diverse group of compounds known to cause peroxisomal proliferation. It has been hypothesized that the common mode of action of these compounds is that they act through an activated coenzyme A (CoA) thioester. Using rat liver microsomal and isolated rat hepatocyte incubation conditions that were effective in producing a COA conjugate of clofibric acid, no corresponding COA derivative could be found for either PFDA or PFOA.

ISSN:0887-2082    

DOI:10.1002/jbt.2570070106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThere is a marked sex difference in the whole‐body elimination of perfluorooctanoic acid (PFOA) in rats, with females excreting the perfluorinated acid much more rapidly (half life [t1/2]<1 day) than males (t1/2=15 days). Our objective was to determine if androgens or estrogens are involved in causing this sex difference in PFOA elimination. Castration of males greatly increased the elimination of [1‐14C]PFOA (9.4 μmiol/kg, i.p.) in urine, demonstrating that a factor produced by the testis was responsible for the slow elimination of PFOA in male rats. Castration plus 17β‐estradiol had no further effect on PFOA elimination whereas castration plus testosterone replacement at the physiologic level reduced PFOA elimination to the same level as rats with intact testes. Thus, in male rats, testosterone exerts an inhibitory effect on renal excretion of PFOA. In female rats, neither ovariectomy nor ovariectomy plus testosterone affected the PFOA urinary elimination, demonstrating that the inhibitory effect of testosterone on PFOA renal excretion is a male‐specific response. Probenecid decreased the high rate of PFOA renal excretion in castrated males but had no effect on male rats with intact testes. We conclude that testosterone is a key determinant of the sex difference in PFOA eliminatio

ISSN:0887-2082    

DOI:10.1002/jbt.2570070107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe distribution of iron and calcium in hepatic subcellular fractions of female rats treated with endrin (1, 2, 3, 4, 10, 10‐hexachloro‐6, 7‐epoxy‐1, 4, 4α, 5, 6, 7, 8, 8α‐octahydroendo, endo‐1, 4:5, 8‐dimethanonaphthalene) was determined. Endrin in corn oil was administered orally to rats in single doses of 3, 4.5, or 6 mg/kg, and the animals were killed at 0, 12, 24, 48, or 72 hr posttreatment. Iron and calcium were determined by atomic absorption spectroscopy. The administration of endrin increased the iron content of mitochondria and decreased the iron content of microsomes and nuclei. Significant increases occurred in the calcium content of mitochondria, microsomes, and nuclei. Thus, the results indicate that with respect to the subcellular distribution of iron and calcium, endrin produces differential effects. Vitamin E succinate administration partially prevented the endrin‐induced hepatic alterations in iron and calcium homeostasis. Endrin also produced dose‐ and time‐dependent increases in the liver and spleen weight/body weight ratios, while decreasing the thymus weight/body weight ratios. The altered distribution of calcium and iron may contribute to the broad range

ISSN:0887-2082    

DOI:10.1002/jbt.2570070108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractWe recently reported that antibody against purified P450 3A1 (P450p) recognizes two electrophoretically distinct proteins (50 and 51 kDa) in liver microsomes from male and female rats, as determined by Western immunoblotting. Depending on the source of the liver microsomes, the 51‐kDa protein corresponded to 3A1 and/or 3A2 which could not be resolved by sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis. The other protein (50 kDa) appears to be another member of the P450 IIIA gene family. Both proteins were markedly intensified in liver microsomes from male or female rats treated with pregnenolone‐16α‐carbonitrile, dexamethasone, troleandomycin, or chlordane. In contrast, treatment of male or female rats with phenobarbital intensified only the 51‐kDa protein. Treatment of male rats with Aroclor 1254 induced the 51‐kDa protein, but suppressed the 50‐kDa form. In addition to their changes in response to inducers, the 50‐ and 51‐kDa proteins also differed in their developmental expression. For example, the 50‐kDa protein was not expressed until weaning (3 weeks), whereas the 51‐kDa protein was expressed even in 1‐week‐old rats. At puberty (between weeks 5 and 6), the levels of the 50‐kDa and 51‐kDa proteins markedly declined in female but not in male rats, which introduced a large sex difference (male>female) in the levels of both proteins. Changes in the level of the 51‐kDa protein were paralleled by changes in the rate of testosterone 2β, 6β‐, and 15β‐hydroxylation. In male rats, the marked increase in the levels of the 50‐kDa protein between weeks 2 and 3 coincided with a three‐ to four fold increase in the rate of testosterone 2β‐, 6β‐, and 15β‐hydroxylation, which suggests that the 50‐kDa protein catalyzes the same pathways of testosterone oxidation as the 51‐kDa protein. However, this developmental increase in testosterone oxidation may have resulted from an activation of the 51‐kDa 3A protein. These results indicate that the two electrophoretically distinct proteins recognized by antibody against P450 3A1 are regulated in a similar but not identical manner, and suggest that the 51‐kDa 3A protein is the major microsomal enzyme responsible for cata

ISSN:0887-2082    

DOI:10.1002/jbt.2570070109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe preceding paper (B. Gemzik, D. Greenway, C. Nevins, and A. Parkinson (1992). Regulation of two electrophoretically distinct proteins recognized by antibody against rat liver cytochrome P450 3A1.J. Biochem. Toxicol, 7(43–52).) described the regulation of two rat liver microsomal proteins (50‐ and 51‐kDa) recognized by antibody against P450 3A1. It was also shown that changes in the levels of the 51‐kDa 3A protein were usually paralleled by changes in the rate of testosterone 2β‐, 6β‐, and 15β‐hydroxylation. The present study demonstrates that age‐ and sex‐dependent changes in the 50‐kDa protein were paralleled by changes in the rate of digitoxin oxidation to digitoxigenin bisdigitoxoside. Induction or suppression of the 50‐kDa protein by treatment of rats with various xenobiotics were also paralleled by changes in the rate of digitoxin oxidation. These results suggest that, contrary to previous assumptions, the conversion of digitoxin to digitoxigenin bisdigitoxoside and the conversion of testosterone to 2β‐, 6β‐ and 15β‐hydroxytestosterone are primarily catalyzed by different forms of P450 3A. Further evidence for this coclusion was obtained from studies in which the suicide inhibitor, chloramphenicol, was administered to mature female rats previously treated with pregnenolone‐16α‐carbonitrile (PCN), which induces both the 50‐kDa and the 51‐kDa protein. Treatment of mature female rats with PCN alone caused a marked increase (16‐ to 18‐fold) in the 6β‐hydroxylation of testosterone and the rate of digitoxin oxidation. Treatment of PCN‐induced rats with chloramphenicol caused a ∼70% decrease in liver microsomal testosterone 6β‐hydroxylation, but had no effect on the rate of conversion of digitoxin to digitoxigenin bisdigitoxoside. The oxidation of testosterone by purified 3A1 (a 51‐kDa protein) was also inhibited by chloramphenicol in a time‐ and reduced nicotinamite adenine dinucleotide phosphate (NADPH)‐dependent manner. In addition to testosterone and chloramphenicol, purified 3A1 also metabolized trole‐andomycin, but it was unable to convert digitoxin to digitoxigenin bisdigitoxoside. Testosterone inhibited the microsomal oxidation of digitoxin, but digitoxin did not inhibit testosterone oxidation. This suggests that testosterone is a substrate for the 3A enzyme that metabolizes digitoxin, but that this form of P450 3A does not contribute significantly to testosterone oxidation by rat liver microsomes. We propose that the 2SbT‐, 6β‐, and 15β‐hydroxylation of testosterone by rat liver microsomes is primarily catalyzed by the 51‐kDa 3A proteins (either 3A1 or 3A2 depending on the source of microsomes)

ISSN:0887-2082    

DOI:10.1002/jbt.2570070110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570070101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY