Fitzpatrick F A
Department of Oncological Sciences & Department of Medicinal Chemistry, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112-0555, USA.
Curr Pharm Des. 2004;10(6):577-88. doi: 10.2174/1381612043453144.
The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors. The levuloglandins are a newer class of products that appear to act via irreversible, covalent attachment to numerous proteins. COX enzymes are clinically important because they are inhibited by aspirin and numerous other non-steroidal anti-inflammatory drugs. This inhibition of COX confers relief from inflammatory, pyretic, thrombotic, neurodegenerative and oncological maladies. About one hundred years have elapsed since Hoffman designed and synthesized acetylsalicylic (aspirin) as an agent intended to lessen the gastrointestinal irritation of salicylates while maintaining their efficacy. During the past forty years systematic advances in our understanding of the structure, regulation and function of COX isoenzymes have enabled the design and synthesis of COX-2 selective inhibitors as agents intended to lessen the gastrointestinal irritation of aspirin and non-selective NSAIDs. This review discusses: 1) how two separate catalytic processes in COX - peroxidase and prostaglandin synthase - act in an integrated fashion manner to generate prostaglandins; 2) why irreversible inactivation of COX is important constitutively and pharmacologically; 3) how cells have managed to use two closely related, almost identical enzymes in ways that discriminate their physiological versus pathological roles; 4) how investigators have used these advances to formulate and test medically important uses for old drugs (i.e. aspirin) and create new ones that still seek to achieve Hoffman's original goal.
环氧化酶同工酶COX - 1和COX - 2催化前列腺素、血栓素和γ-戊酮前列腺素的形成。前列腺素是自体活性物质介质，通过与G蛋白偶联膜受体的可逆相互作用，几乎影响所有已知的生理和病理过程。γ-戊酮前列腺素是一类较新的产物，似乎通过与多种蛋白质的不可逆共价结合发挥作用。COX酶在临床上很重要，因为它们会受到阿司匹林和许多其他非甾体抗炎药的抑制。对COX的这种抑制作用可缓解炎症、发热、血栓形成、神经退行性变和肿瘤疾病。自霍夫曼设计并合成乙酰水杨酸（阿司匹林）以减轻水杨酸盐的胃肠道刺激并同时保持其疗效以来，已经过去了大约一百年。在过去的四十年里，我们对COX同工酶的结构、调节和功能的理解有了系统性进展，这使得COX - 2选择性抑制剂得以设计和合成，旨在减轻阿司匹林和非选择性非甾体抗炎药的胃肠道刺激。本综述讨论：1）COX中的两个独立催化过程——过氧化物酶和前列腺素合酶——如何以整合的方式作用以生成前列腺素；2）COX的不可逆失活在组成上和药理学上为何重要；3）细胞如何设法以区分其生理与病理作用的方式使用两种密切相关、几乎相同的酶；4）研究人员如何利用这些进展来制定和测试旧药（即阿司匹林）的医学重要用途，并创造仍试图实现霍夫曼最初目标的新药。
