The endocrine-disrupting activities of bisphenol A (BPA) and 19 related compounds were comparatively examined by means of different in vitro and in vivo reporter assays. BPA and some related compounds exhibited estrogenic activity in human breast cancer cell line MCF-7, but there were remarkable differences in activity. Tetrachlorobisphenol A (TCBPA) showed the highest activity, followed by bisphenol B, BPA, and tetramethylbisphenol A (TMBPA); 2,2-bis(4-hydroxyphenyl)-1-propanol, 1,1-bis(4-hydroxyphenyl)propionic acid and 2,2-diphenylpropane showed little or no activity. Anti-estrogenic activity against 17beta-estradiol was observed with TMBPA and tetrabromobisphenol A (TBBPA). TCBPA, TBBPA, and BPA gave positive responses in the in vivo uterotrophic assay using ovariectomized mice. In contrast, BPA and some related compounds showed significant inhibitory effects on the androgenic activity of 5alpha-dihydrotestosterone in mouse fibroblast cell line NIH3T3. TMBPA showed the highest antagonistic activity, followed by bisphenol AF, bisphenol AD, bisphenol B, and BPA. However, TBBPA, TCBPA, and 2,2-diphenylpropane were inactive. TBBPA, TCBPA, TMBPA, and 3,3'-dimethylbisphenol A exhibited significant thyroid hormonal activity towards rat pituitary cell line GH3, which releases growth hormone in a thyroid hormone-dependent manner. However, BPA and other derivatives did not show such activity. The results suggest that the 4-hydroxyl group of the A-phenyl ring and the B-phenyl ring of BPA derivatives are required for these hormonal activities, and substituents at the 3,5-positions of the phenyl rings and the bridging alkyl moiety markedly influence the activities.

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-In order to investigate the effect of sunlight on the persistence and ecotoxicity of pharmaceuticals contaminating the aquatic environment, we exposed nine pharmaceuticals (acetaminophen (AA), amiodarone (AM), dapsone (DP), dexamethasone (DX), indomethacin (IM), naproxen (NP), phenytoin (PH), raloxifene (RL), and sulindac (SL)) in aqueous media to sunlight and to ultraviolet (UV) irradiation at 254, 302 or 365 nm (UV-C, UV-B or UV-A, respectively). Degradation of the pharmaceuticals was monitored by means of high-performance liquid chromatography (HPLC). Sunlight completely degraded AM, DP and DX within 6 hr, and partly degraded the other pharmaceuticals, except AA and PH, which were not degraded. Similar results were obtained with UV-B, while UV-A was less effective (both UV-A and -B are components of sunlight). All the pharmaceuticals were photodegraded by UV-C, which is used for sterilization in sewage treatment plants. Thus, the photodegradation rates of pharmaceuticals are dependent on both chemical structure and the wavelength of UV exposure. Toxicity assay using the luminescent bacteria test (ISO11348) indicated that UV irradiation reduced the toxicity of some pharmaceuticals to aquatic organisms by decreasing their amount (photodegradation) and increased the toxicity of others by generating toxic photoproduct(s). These results indicate the importance of investigating not only parent compounds, but also photoproducts in the risk assessment of pharmaceuticals in aquatic environments.

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ABSTRACT:Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. ). Elimination half-life (t 1/2 ) after intravenous administration also showed a good correlation (r 2 ‫؍‬ 0.886, p ‫؍‬ 1.506 ؋ 10 ؊4) between humans and PXB mice. The rank order of CL and t 1/2 in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.

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