Liu Y, Levy G N, Weber W W
Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA.
Biochem Biophys Res Commun. 1995 Oct 4;215(1):346-54. doi: 10.1006/bbrc.1995.2472.
Prostaglandin endoperoxide H synthase is the key enzyme in the conversion of arachidonic acid to tissue prostanoids. Two isoforms of prostaglandin endoperoxide H synthase have been identified: PHS-1 is constitutively expressed in most tissues under normal physiological conditions and PHS-2 is expressed in response to inflammatory agents, tumor promotors, and other agents related to mitogenesis. Previous work demonstrated that PHS-1 can activate arylamine carcinogens. We report here that PHS-2 can also activate an arylamine carcinogen to form DNA adducts. This is shown by: (1) use of purified ovine PHS-2 to form DNA adducts; (2) increased DNA adduct formation, PHS-2 mRNA, and PHS-2 protein after treatment of HUVEC cells with the PHS-2 inducer PMA; and (3) transient expression of PHS-2 cDNA in COS-1 cells gave rise to both elevations of PHS-2 enzyme protein and DNA adduct formation. Finally, two PHS inhibitors, aspirin and indomethacin, showed significant inhibition of PHS-2-mediated DNA adduct formation.
前列腺素内过氧化物合酶是将花生四烯酸转化为组织前列腺素的关键酶。已鉴定出前列腺素内过氧化物合酶的两种同工型：PHS-1在正常生理条件下在大多数组织中组成性表达，而PHS-2在炎症介质、肿瘤促进剂和其他与有丝分裂相关的介质作用下表达。先前的研究表明，PHS-1可激活芳胺致癌物。我们在此报告，PHS-2也可激活一种芳胺致癌物以形成DNA加合物。这通过以下方式得以证明：（1）使用纯化的绵羊PHS-2形成DNA加合物；（2）用PHS-2诱导剂PMA处理人脐静脉内皮细胞（HUVEC）后，DNA加合物形成增加、PHS-2 mRNA和PHS-2蛋白增加；（3）在COS-1细胞中瞬时表达PHS-2 cDNA导致PHS-2酶蛋白升高和DNA加合物形成。最后，两种PHS抑制剂阿司匹林和吲哚美辛对PHS-2介导的DNA加合物形成有显著抑制作用。
