Zhang Wei V, Ramzan Iqbal, Murray Michael
Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
J Pharmacol Exp Ther. 2007 Aug;322(2):770-7. doi: 10.1124/jpet.107.124024. Epub 2007 May 23.
Hepatic lipid infiltration (steatosis) is a complication of the metabolic syndrome and can progress to nonalcoholic steatohepatitis and severe liver injury. Microsomal cytochrome P450 (P450) drug oxidases are down-regulated in experimental steatosis. In this study we evaluated the separate and combined effects of lipid accumulation and P450 down-regulation on the microsomal oxidation of the antipsychotic agent clozapine (CLZ), the use of which is associated with an increased incidence of the metabolic syndrome. Several important drug oxidizing P450s were down-regulated, and the formation of N-desmethyl-CLZ (norCLZ) and CLZ N-oxide was decreased in microsomal fractions from orotic acid-induced early steatotic rat liver. Inclusion of lipids extracted from steatotic, but not control, liver decreased the free concentration of CLZ in microsomes and suppressed norCLZ formation; CLZ N-oxidation was unchanged. Triglycerides increased in steatotic liver to 15-fold of control, whereas increases in the monounsaturated oleic acid to 10-fold of control and total polyunsaturated and saturated fatty acids to 4- and 5-fold of control also occurred. Addition of triglycerides containing esterified omega-6 and omega-3 fatty acids inhibited the microsomal formation of norCLZ but not that of CLZ N-oxide; triglycerides esterified with unsaturated and monounsaturated fatty acids were inactive. Thus, drug oxidation may be suppressed in steatosis by P450 down-regulation and the accumulation of polyunsaturated fatty esters. In contrast, the activity of the flavin-containing monooxygenase that mediates CLZ N-oxidation was unimpaired. Lipid deposition in livers of patients with the metabolic syndrome may necessitate dosage adjustments for toxic drugs, including CLZ.
肝脂质浸润（脂肪变性）是代谢综合征的一种并发症，可进展为非酒精性脂肪性肝炎和严重肝损伤。微粒体细胞色素P450（P450）药物氧化酶在实验性脂肪变性中表达下调。在本研究中，我们评估了脂质蓄积和P450下调分别及联合作用对抗精神病药物氯氮平（CLZ）微粒体氧化的影响，氯氮平的使用与代谢综合征发病率增加有关。几种重要的药物氧化P450表达下调，在乳清酸诱导的早期脂肪变性大鼠肝脏微粒体组分中，N-去甲基氯氮平（去甲氯氮平）和氯氮平N-氧化物的形成减少。加入从脂肪变性肝脏而非对照肝脏中提取的脂质可降低微粒体中CLZ的游离浓度并抑制去甲氯氮平的形成；氯氮平N-氧化未受影响。脂肪变性肝脏中的甘油三酯增加至对照的15倍，而单不饱和油酸增加至对照的10倍，总多不饱和脂肪酸和饱和脂肪酸分别增加至对照的4倍和5倍。添加含有酯化ω-6和ω-3脂肪酸的甘油三酯可抑制微粒体中去甲氯氮平的形成，但不影响氯氮平N-氧化物的形成；用不饱和脂肪酸和单不饱和脂肪酸酯化的甘油三酯无活性。因此，脂肪变性时药物氧化可能因P450下调和多不饱和脂肪酸酯蓄积而受到抑制。相比之下，介导氯氮平N-氧化的含黄素单加氧酶的活性未受损害。代谢综合征患者肝脏中的脂质沉积可能需要对包括氯氮平在内的毒性药物进行剂量调整。
