University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics, MS-1018, Room KLSIC-4061, 2146 W. 39th Ave, Kansas City, KS 66160, USA.
Expert Opin Drug Metab Toxicol. 2010 Apr;6(4):483-94. doi: 10.1517/17425250903578642.
The CYP isoforms that are selectively induced following exposure to structurally-diverse chemicals often are the ones capable of metabolizing these chemicals. However, the molecular mechanism underlying this apparent functional coupling is not understood at present.
Three hypotheses are developed to explain the complex process of selective chemical induction of CYPs: i) each inducible CYP may have a corresponding intracellular receptor that interacts with the inducer chemical and mediates the selective induction of this CYP; ii) each inducible CYP and its corresponding receptor may share highly similar steric structures for their substrate/inducer-binding sites and iii) each chemically-inducible CYP gene may have distinct genomic response element(s) that interact selectively with the corresponding receptor.
The readers are introduced to a novel theoretical framework that offers a plausible mechanistic explanation at the molecular level concerning the complex process of how an organism selectively activates the biosynthesis of certain CYP isoform(s) that can effectively metabolize a chemical to which the organism is exposed.
The theoretical framework developed herein seeks to ignite additional critical thinking on this important research subject as well as to promote experimental testing of the proposed theories in the future. Undoubtedly, these studies will enhance the understanding of the molecular mechanisms for the selective induction of CYP enzymes by chemicals.
在接触结构多样的化学物质后，被选择性诱导的 CYP 同工酶通常是能够代谢这些化学物质的同工酶。然而，目前尚不清楚这种明显的功能偶联的分子机制。
提出了三种假说来解释 CYP 的选择性化学诱导的复杂过程：i）每种可诱导的 CYP 可能都有相应的细胞内受体，与诱导剂化学物质相互作用，介导这种 CYP 的选择性诱导；ii）每种可诱导的 CYP 和其相应的受体可能具有高度相似的空间结构，用于其底物/诱导剂结合位点；iii）每种化学诱导的 CYP 基因可能具有独特的基因组反应元件（s），与相应的受体选择性相互作用。
读者将了解到一个新颖的理论框架，该框架在分子水平上提供了一个合理的机制解释，说明生物体如何选择性地激活某些 CYP 同工酶的生物合成，这些同工酶能够有效地代谢生物体所接触的化学物质。
本文提出的理论框架旨在激发对这一重要研究课题的更多批判性思考，并促进未来对所提出理论的实验检验。这些研究无疑将增强对化学物质选择性诱导 CYP 酶的分子机制的理解。
