Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the omega- and (omega-1)-hydroxylation of fatty acids and the omega-hydroxylation of prostaglandins E1 and F2 alpha.
Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the omega- and (omega-1)-hydroxylation of fatty acids and the omega-hydroxylation of prostaglandins E1 and F2 alpha.
复制标题
氯贝特诱导的大鼠肝 P450 IVA1 和 IVA3 催化脂肪酸的 omega-和 (omega-1)-羟基化以及前列腺素 E1 和 F2 α 的 omega-羟基化。
DOI：
--
复制
发表时间：
1990
影响因子：
6.5
通讯作者：
F. J. Gonzalez
中科院分区：
文献类型：
--
作者：
T. Aoyama;J. Hardwick;S. Imaoka;Y. Funae;Gelboin Hv;F. J. Gonzalez
细胞色素P450 IVA 1和IVA 3显示72%的氨基酸序列相似性，并在用降血脂药物氯贝丁酯治疗的大鼠肝脏中表达。IVA 1和IVA 3的催化活性通过使用牛痘病毒的cDNA定向表达来检测。cDNA表达的IVA 1和IVA 3在SDS-聚丙烯酰胺凝胶上的相对分子质量分别为51，500和52，000。这两种酶显示减少，CO结合的吸收光谱与λ max为452.5 nm。IVA 1和IVA 3在ω和ω-1位置羟基化月桂酸，具有约12.5的当量ω/ω-1比。IVA 1的底物周转率为21 min-1，约为IVA 3的4倍。棕榈酸的omega和omega-1羟基化也被这些P450催化，IVA 1和IVA 3的两种代谢物的组合周转数分别为45 min-1或18 min-1。IVA 1对棕榈酸酯的omega/omega-1氧化比为1.25，几乎是IVA 3的4倍。这些酶还催化生理上重要的类花生酸E1和F2 α的ω氧化，其转化率约为脂肪酸氧化计算值的十分之一。没有产生ω-1羟基代谢物。这些研究表明，P450酶IVA 1和IVA 3能够催化脂肪酸和洋地黄素的氧化。
Cytochromes P450IVA1 and IVA3 display 72% amino acid sequence similarity and are expressed in livers of rats treated with the hypolipidemic drug clofibrate. The catalytic activities of IVA1 and IVA3 were examined by cDNA-directed expression using vaccinia virus. cDNA-expressed IVA1 and IVA3 had relative Mrs of 51,500 and 52,000, respectively, on SDS-polyacrylamide gels. Both enzymes displayed reduced, CO-bound absorption spectra with lambda max of 452.5 nm. IVA1 and IVA3 hydroxylated lauric acid at the omega and omega-1 positions with equivalent omega/omega-1 ratios of about 12.5. IVA1 had a substrate turnover of 21 min-1 which was about fourfold higher than that of IVA3. The omega and omega-1 hydroxylation of palmitic acid was also catalyzed by these P450s with combined turnover numbers for both metabolites of 45 min-1 or 18 min-1 for IVA1 and IVA3, respectively. The omega/omega-1 oxidation ratio of IVA1 for palmitate was 1.25 which was almost fourfold higher than that obtained for IVA3. These enzymes also catalyzed omega oxidation of the physiologically important eicosanoids prostaglandins E1 and F2 alpha with turnover numbers of about one-tenth those calculated for fatty acid oxidations. No omega-1 hydroxy metabolites were produced. These studies indicate that the P450 enzymes IVA1 and IVA3 are able to catalyze the oxidations of both fatty acids and prostaglandins.