Xu Fengyun, Ng Valerie Y, Kroetz Deanna L, de Montellano Paul R Ortiz
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-2280, USA.
J Pharmacol Exp Ther. 2006 Aug;318(2):835-9. doi: 10.1124/jpet.106.104976. Epub 2006 May 17.
The saturated C20 isoprenoid phytanic acid is physiologically derived from phytol released in the degradation of chlorophyll. The presence of a C-3 methyl group in this substrate blocks normal beta-oxidation, so phytanic acid degradation primarily occurs by initial peroxisomal alpha-oxidation to shift the register of the methyl group. However, individuals with Refsum's disease are genetically deficient in the required phytanoyl-CoA alpha-hydroxylase and suffer from neurological pathologies caused by the accumulation of phytanic acid. Recent work has shown that phytanic acid can also be catabolized by a pathway initiated by omega-hydroxylation of the hydrocarbon chain, followed by oxidation of the alcohol to the acid and conventional beta-oxidation. However, the enzymes responsible for the omega-hydroxylation of phytanic acid have not been identified. In this study, we have determined the activities of all of the rat and human CYP4A enzymes and two of the rat CYP4F enzymes, with respect to the omega-hydroxylation of phytanic acid. Furthermore, we have shown that the ability to omega-hydroxylate phytanic acid is elevated in microsomes from rats pretreated with clofibrate. The results support a possible role for CYP4 enzyme elevation in the elimination of phytanic acid in Refsum's disease patients.
饱和的C20类异戊二烯植烷酸在生理上源自叶绿素降解过程中释放的叶绿醇。该底物中C-3甲基的存在阻碍了正常的β-氧化，因此植烷酸的降解主要通过最初的过氧化物酶体α-氧化来改变甲基的位置。然而，患有Refsum病的个体在基因上缺乏所需的植烷酰辅酶Aα-羟化酶，并因植烷酸的积累而患有神经病理学疾病。最近的研究表明，植烷酸也可以通过烃链的ω-羟基化引发的途径进行分解代谢，随后醇氧化为酸并进行常规的β-氧化。然而，负责植烷酸ω-羟基化的酶尚未被鉴定。在本研究中，我们测定了所有大鼠和人类CYP4A酶以及两种大鼠CYP4F酶对植烷酸ω-羟基化的活性。此外，我们已经表明，用氯贝丁酯预处理的大鼠微粒体中植烷酸ω-羟基化的能力有所提高。这些结果支持了CYP4酶升高在Refsum病患者植烷酸消除中的可能作用。
