Tomaszewski K E, Melnick R L
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Biochim Biophys Acta. 1994 Jan 13;1220(2):118-24. doi: 10.1016/0167-4889(94)90126-0.
The mechanisms of peroxisomal induction and hypolipidaemia caused by treatment with peroxisome proliferators, such as nafenopin and clofibrate, remain to be elucidated. Proposed mechanisms include receptor-mediated processes or adaptations resulting from disruption of hepatic lipid metabolism. The latter mechanism was investigated in a series of in vitro studies. Incubation of primary rat hepatocytes with various carboxyl-containing compounds revealed no clear common factor which imparted potency as a peroxisomal inducer. Inhibitors of fatty acyl-CoA synthetase, norepinephrine and desulpho-CoA, however, decreased the level of peroxisomal induction by nafenopin in rat hepatocytes, suggesting that activation of carboxyl-containing compounds to their CoA thioesters may be a necessary step in initiating peroxisome proliferation. Coenzyme A thioesters of nafenopin, clofibric acid and other carboxyl-containing chemicals were synthesised and found to inhibit the activity of acetyl-CoA carboxylase to varying degrees. The CoA thioester of nafenopin was the most potent inhibitor among this group (Ki = 1.45 x 10(-5) M), but weaker than palmitoyl-CoA (Ki = 2.22 x 10(-6) M), the feedback inhibitor of acetyl-CoA carboxylase. Hypolipidaemia caused by treatment with peroxisome proliferators may, therefore, be related to inhibition of fatty-acid synthesis by the corresponding CoA thioester derivative.
由过氧化物酶体增殖剂（如萘酚平与氯贝丁酯）治疗所引起的过氧化物酶体诱导和降血脂作用机制仍有待阐明。提出的机制包括受体介导的过程或因肝脏脂质代谢紊乱而产生的适应性变化。后一种机制在一系列体外研究中得到了探究。用各种含羧基化合物孵育原代大鼠肝细胞，未发现赋予其作为过氧化物酶体诱导剂效力的明确共同因素。然而，脂肪酰辅酶A合成酶抑制剂、去甲肾上腺素和脱硫辅酶A降低了萘酚平在大鼠肝细胞中诱导过氧化物酶体的水平，这表明含羧基化合物激活为其辅酶A硫酯可能是启动过氧化物酶体增殖的必要步骤。合成了萘酚平、氯贝酸和其他含羧基化学物质的辅酶A硫酯，并发现它们能不同程度地抑制乙酰辅酶A羧化酶的活性。萘酚平的辅酶A硫酯是该组中最有效的抑制剂（Ki = 1.45×10⁻⁵ M），但比乙酰辅酶A羧化酶的反馈抑制剂棕榈酰辅酶A（Ki = 2.22×10⁻⁶ M）弱。因此，过氧化物酶体增殖剂治疗引起的降血脂作用可能与相应的辅酶A硫酯衍生物抑制脂肪酸合成有关。
