Okita R T, Okita J R
Department of Pharmaceutical Sciences, Washington State University, Pullman 99164-6534, USA.
Curr Drug Metab. 2001 Sep;2(3):265-81. doi: 10.2174/1389200013338423.
The Cytochrome P450 4A subfamily is one of eighteen subfamilies in the CYP4 family and presently consists of twenty individual forms in nine different mammalian species. The major substrates for CYP4A forms are fatty acids, but recent studies have shown other non-fatty acid substrates may be metabolized by specific CYP4A forms. The physiological and metabolic functions of the CYP4A subfamily have not been elucidated, but the ability of CYP4A forms to metabolize medium and long chain length fatty acids at their omega (omega)-carbon atom has generated significant interest because of the possible role that omega-hydroxylated fatty acids may have in cell signalling processes and as an alternative pathway for fatty acid metabolism. A number of different compounds or physiological conditions have been shown to regulate the expression of CYP4A forms in liver and/or kidney. Several CYP4A forms may serve as a marker for the exposure to compounds that are classified as peroxisome proliferators. There is also considerable interest why multiple CYP4A forms exist in different tissues. Recent studies in the rat and human indicate that other CYP4 forms besides CYP4A forms may be responsible for the metabolism of arachidonic acid to its omega-hydroxy product. The focus of this review will be to summarize recent studies that have characterized the substrate specificity of rat, rabbit and human CYP4A forms and discuss the significance of CYP4A-mediated hydroxylation of fatty acids. In addition, dietary effects or novel compounds that have been reported to regulate CYP4A expression in the rat and mouse will be discussed.
细胞色素P450 4A亚家族是CYP4家族的18个亚家族之一，目前在9种不同的哺乳动物物种中由20种个体形式组成。CYP4A形式的主要底物是脂肪酸，但最近的研究表明，其他非脂肪酸底物可能被特定的CYP4A形式代谢。CYP4A亚家族的生理和代谢功能尚未阐明，但由于ω-羟基化脂肪酸在细胞信号传导过程中可能发挥的作用以及作为脂肪酸代谢的替代途径，CYP4A形式在其ω（ω）碳原子处代谢中长链脂肪酸的能力引起了极大的兴趣。已证明许多不同的化合物或生理条件可调节肝脏和/或肾脏中CYP4A形式的表达。几种CYP4A形式可作为接触被归类为过氧化物酶体增殖剂的化合物的标志物。对于不同组织中为何存在多种CYP4A形式也有相当大的兴趣。最近在大鼠和人类中的研究表明，除了CYP4A形式之外的其他CYP4形式可能负责将花生四烯酸代谢为其ω-羟基产物。本综述的重点将是总结最近表征大鼠、兔子和人类CYP4A形式底物特异性的研究，并讨论CYP4A介导的脂肪酸羟基化的意义。此外，还将讨论已报道的调节大鼠和小鼠中CYP4A表达的饮食效应或新型化合物。
