Comparative physiology, pharmacology and toxicology of b2;-blockers: Mammals versus fish

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• 作者：Stewart F. Owen ; Emma Giltrow ; Duane B. Huggett ; Thomas H. Hutchinson ; JoAnne Saye ; Matthew J. Winter ; John P. Sumpter
• 关键词：Pharmaceuticals ; Drugs ; Cardiovascular ; Ecotoxicology ; Aquatic ; Water
• 刊名：Aquatic Toxicology
• 出版年：2007
• 出版时间：15 May 2007
• 年：2007
• 卷：82
• 期：3
• 页码：145-162
• 全文大小：1479 K

文摘

On the premise that human medicines may potentially induce similar pharmacological and toxicological profiles in fish and other lower vertebrates, we have applied this comparative approach to beta-adrenergic receptor antagonists (‘b2;-blockers’) which are widely detected in surface waters. While reported concentrations of b2;-blockers are typically in the low ng/L range, data are needed to define whether this contamination poses any long-term threat to fish or other aquatic organisms. We argue that gathering experimental data in fish for these compounds may be done more efficiently by considering mammalian toxicology data. Extensive mammalian pharmacological and toxicological studies are central to development of medicines and these can provide valuable information to guide ecotoxicological studies. For b2;-blockers, we can increasingly exploit the knowledge from molecular approaches to understand phenotypes and functions of adrenergic receptors in mammals versus fish. Some b2;-adrenergic receptors have been characterised in fish using both traditional molecular cloning methods, or via mining of genomic sequences from various organisms. These approaches demonstrate that fish have b2;-adrenergic receptors very similar to those present in mammals. Since we believe that any effects of b2;-blockers in fish are most likely to be mediated via b2;-adrenergic receptors, it is the physiological processes regulated by these receptors that are most likely to be affected. Thus, cardiovascular dysfunction is one possible consequence of exposure of fish to these compounds, leading to impaired fitness (e.g. reduced growth and fecundity). More broadly, conceptual mathematical models suggest it might be possible to predict plasma concentrations of b2;-blockers in fish from mammals, although these models cannot be regarded as reliable until thoroughly validated. Experimental data are therefore urgently needed to define plasma levels and metabolism of b2;-blockers compared in fish with mammals. Finally, accurate citation of CAS numbers is essential for pharmaceuticals in order to compare nominal concentration data in terms of either the drug free base or the drug salt complex.