摘要:

AbstractFluconazole is an orally active bis‐triazole antifungal agent that acts by selective inhibition of lanosterol 14α‐demethylase, a key enzyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague‐Dawley rats, fluconazole decreased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of these changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights of hormone‐sensitive organs and circulating levels of 17β‐estradiol. The decreases in mammary tumors are probably a consequence of aromatase inhibition by fluconazole at high dose levels. The tumor effects observed in this study are extremely unlikely to be of relevance to humans, since the hormone effects observed in this study do not occur in humans treated with therapeutic dose levels of fluconazole. This study illustrates the importance of seeking a mechanistic interpretation of rodent tumor findings, which may then be assessed for its relevance to the clinical use of a drug. © 1994 Wil

ISSN:0270-3211    

DOI:10.1002/tcm.1770140602

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

年代:1994

数据来源: WILEY

摘要:

AbstractWe have examined the effect of protein kinase (PKC) depletion in SV40‐transformed Djungarian hamster fibroblasts (DM15 cells) on the level of gap junction permeability, C×43 electrophoretic mobility, and cell sensitivity to different uncoupling stimuli. After 24 hr exposure to 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), the total PKC activity in DM15 cells was reduced to 20–25% in comparison with intact cells. In PKC‐depleted cells the level of dye coupling was 30–40% higher than in the same untreated cultures. Western blot analysis revealed multiple forms of the gap junction protein connexin 43, which correspond to known phosphorylated and dephosphorylated forms of this protein. No decrease in the level of connexin 43 phosphorylation after PKC depletion was observed. TPA (10−7g/ml), mezerein (10−7g/ml), teleocidin (10−8g/ml), Ca‐ionophore A23187 (10−6g/ml), insecticide 1,1,1‐trichloro‐2,2‐bis‐(p‐chlorphenyl)‐ethane (DDT) (10−4g/ml), and nigericin (10−5M in hydrolysate lactalbumin solution, pH 6.3) induced a four‐to six‐fold decrease in the number of recipient cells in the dye‐coupling assay. PKC‐depleted cells became almost completely resistant to the uncoupling effect of mezerein, teleocidin, and A23187, as well as to new exposure to TPA, and became partially resistant to the effect of DDT. Nigericin inhibited intercellular communication between PKC‐depleted cells to the same extent as between control cells. Thus, in the cell system studied, PKC plays a certain role in maintaining the basal level of gap junction permeability and has an important significance as a mediator of the uncoupling effects of such substances as TPA,

ISSN:0270-3211    

DOI:10.1002/tcm.1770140603

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

年代:1994

数据来源: WILEY

摘要:

AbstractEthylnitrosourea (ENU) was i.p. injected into ICR female mice at 25 or 50 mg/kg on day 10 of gestation, and male newborns treated with ENU at the embryonic stage were obtained. The treated males were aged for 10 weeks and then mated to untreated females of the same strain. The male germ cells used in the copulation correspond to primordial germ cells (PGC) at the time of ENU treatment. The F1offspring were sampled as fetuses on day 18 of gestation and inspected for external and skeletal malformations. Evidence of F1teratogenesis due to the mutagenized PGC was obtained when the fetuses from the males treated with 25 mg ENU/kg were inspected the frequencies of skeletally malformed fetuses in the ENU‐treated series and the control being, respectively, 1.0% (14/1,360) and 0.3% (3/1,017). The fetuses from 50 mg/kg‐treated males did not show a significant increase in malformations, most probably reflecting a high vulnerability of PGC to the killing effect of ENU. The findings in this study suggest that germ cell stage at PGC is at risk for the induction of congenital malformations by environmental chemicals. © 1994 Wiley‐Lis

ISSN:0270-3211    

DOI:10.1002/tcm.1770140604

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

年代:1994

数据来源: WILEY

摘要:

AbstractPrevious work demonstrated that rat embryos were more susceptible to the growth retardation effect of the synthetic glucocorticoid dexamethasone (DEX) in vivo than were mouse embryos. The purpose of this study was to examine this species difference using an in vitro system. Embryos of CD rats and CD‐1 mice were cultured in a whole embryo culture system with concentrations of DEX from 5 to 250 μg/ml. Rat embryos were explanted on day 9 of gestation (GD 9: plug day = GD 0), while mouse embryos were removed on GD 8. After 48 h in culture, each viable embryo was evaluated for morphological score, and the number of somite pairs, crown‐rump, and head lengths, as well as DNA and protein concentrations were determined. A reduced morphological score was observed for mouse embryos at 5 μg DEX/ml, but a significant decrease in this parameter was only observed at DEX concentrations of ⩾ 100 μg/ml in rat embryos. Significant reductions in the number of somite pairs were observed at 25 μg/ml for mouse embryos and 100 μg/ml for rat embryos. Crown‐rump and head lengths as well as DNA and protein concentrations were significantly decreased at 100 μg/ml in mouse embryos and 150 μg/ml in rat embryos. Therefore, in vitro mouse embryos were adversely affected by lower concentrations of DEX than were rat embryos for each of the six end points examined in this study. This species sensitivity in vitro could be due to inherent genetic differences or to the slightly different developmental stages evaluated using the culture system. The species sensitivity observed in vivo may be due to a maternal difference in the pharmacodynamics of the drug. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as suh, is in the public domain in the United

ISSN:0270-3211    

DOI:10.1002/tcm.1770140605

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

年代:1994

数据来源: WILEY

摘要:

AbstractPyrazole and 4‐methylpyrazole (4‐MP) are in vivo and in vitro inhibitors of alcohol dehydrogenase activity in mammals. The fruitflyDrosophila melanogasterhas been used to demonstrate the influence of genetic variation in alcohol dehydrogenase alleles on the results of larval treatment with pyrazole and 4‐MP. Genetic polymorphism of organisms involved in experiments with teratogenic and toxic agents is not often considered. Administration of pyrazole to larvae of isogenicD. melanogasterstrains, differing mainly in theirAdhalleles, caused largeNotch‐like teratogenic aberrations, macrochaetae multiplication, and pupal mortality. The level of teratogenicity and developmental‐toxicity of pyrazole was both concentration andAdh‐genotype‐dependent. The strain with the highest ADH activity showed smaller effects after the treatments with the two concentrations used. 4‐MP does not cause morphological aberrations, although treatment of larvae with an isogenic background caused a high pupal mortality due to non‐differentiated material in the pupal case. © 19

ISSN:0270-3211    

DOI:10.1002/tcm.1770140606

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

年代:1994

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770140601

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

年代:1994

数据来源: WILEY