DRUG-METABOLIZING-ENZYMES IN LIGAND-MODULATED TRANSCRIPTION
DRUG-METABOLIZING-ENZYMES IN LIGAND-MODULATED TRANSCRIPTION
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DOI：
10.1016/0006-2952(94)90434-0
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发表时间：
1994-01-13
影响因子：
5.8
通讯作者：
NEBERT, DW
中科院分区：
文献类型：
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作者：
NEBERT, DW
编码许多所谓的药物代谢酶 (DME) 的基因同时存在于原核生物和真核生物中，这表明这些基因在动植物分化之前（估计大约 12 亿年前）以及药物的使用和商业开发之前很久就在这个星球上出现了 35 亿年以上。那么，DME 的真正功能是什么？几年前，我提出 DME 是众多信号转导途径的调节级联的上游，即维持每个细胞中空气小非蛋白质内源配体 (M(r) = 250+/-200) 生理上“安全”或“可接受”的稳态水平所必需的。无数的外来化学物质和药物模仿这些小的内源性配体，从而与特定受体结合，并在激活或抑制影响生长、分化、细胞凋亡、稳态和神经内分泌功能的基因中充当激动剂或拮抗剂。本综述讨论了与该理论一致且在之前的综述中未描述的其他例子，包括：（i）昆虫与植物共生； (ii) 芳香烃响应性[Ah]电池中基因之间的“串扰”； (iii) 涉及花生四烯酸级联的信号转导途径； (iv) 在致癌物筛选研究中解释为什么许多测试化合物的最大或半最大耐受剂量（MTD、MTD(50)）可能导致实验动物细胞分裂和肿瘤发生。
Genes encoding many of the so-called drug-metabolizing enzymes (DMEs) are present in both prokaryotes and eukaryotes, suggesting that these genes arose on this planet more than 3.5 billion years age-long before animal-plant divergence (estimated to be about 1.2 billion years ago) and long before the use and commercial development of drugs. What, therefore, are the real functions of DMEs? Several years ago I proposed that DMEs are upstream in the regulatory cascade of numerous signal transduction pathways, i.e. necessary for maintaining physiologically ''safe'', or ''acceptable'', steady-state levels of air small non-protein endogenous ligands (M(r) = 250+/-200) in each cell. Innumerable foreign chemicals and drugs mimic these small endogenous ligands, thus binding to a particular receptor and acting either as an agonist or antagonist in activating or inhibiting genes effecting growth, differentiation, apoptosis, homeostasis and neuroendocrine functions. Discussed in this review are additional examples consistent with this theory and not described in previous reviews, including: (i) insect-plant symbiosis; (ii) ''cross-talk'' amongst genes in the aromatic hydrocarbon-responsive [Ah] battery; (iii) signal transduction pathways involving the arachidonic acid cascade; and (iv) the explanation in carcinogen-screening studies as to why a maximum, or half maximum, tolerated dose (MTD, MTD(50)) of many test compounds might cause cell division and tumorigenesis in experimental animals.