Mitchell F E, Bridges J W, Hinton R H
Biochem Pharmacol. 1986 Sep 1;35(17):2941-7. doi: 10.1016/0006-2952(86)90490-9.
In cultured hepatocytes, as in vivo, mono-2-ethylhexyl phthalate (MEHP) and its straight chain analogues mono-n-hexyl phthalate (MnHP) and mono-n-octyl phthalate (MnOP) each cause accumulation of lipid but only MEHP produces significant induction of peroxisomal fatty acid oxidizing enzymes. To elucidate the mechanisms underlying this lipid accumulation we investigated the effects of these phthalates and the drug clofibric acid on fatty acid metabolism in suspensions of isolated hepatocytes. The effects were found to be markedly dependent on the nutritional state of the animals from which the hepatocytes were isolated. In hepatocytes isolated from animals fasted overnight, or animals fed ab libitum but killed at approximately 2.30 p.m., MEHP, MnHP, MnOP and clofibric acid each caused a marked rapid stimulation of fatty acid oxidation and the synthesis of triglycerides in hepatocytes when incubated in Hanks saline. Export of very low density lipoprotein (VLDL) from the cells was either unchanged or somewhat reduced. In contrast, in hepatocytes isolated from rats fed ad libitum but killed at approximately 9.30 a.m. MEHP and clofibric acid did not alter fatty acid oxidation or triglyceride synthesis, while MnOP and MnHP increased triglyceride synthesis but decreased fatty acid oxidation. The effects of fasting were largely abolished by incubations of the cells in a complete tissue culture medium (Liebowitz L-15). The results suggest that MEHP and its straight chain analogues can, either as the free acid or the CoA ester, mimic the action of fatty acids in the allosteric regulation of fatty acid metabolism.
在培养的肝细胞中，与在体内情况一样，邻苯二甲酸单-2-乙基己酯（MEHP）及其直链类似物邻苯二甲酸单正己酯（MnHP）和邻苯二甲酸单正辛酯（MnOP）均可导致脂质蓄积，但只有MEHP能显著诱导过氧化物酶体脂肪酸氧化酶。为阐明这种脂质蓄积的潜在机制，我们研究了这些邻苯二甲酸酯和药物氯贝酸对分离的肝细胞悬液中脂肪酸代谢的影响。结果发现，这些影响明显取决于分离肝细胞所取动物的营养状态。在从禁食过夜的动物或随意进食但在下午约2:30处死的动物分离的肝细胞中，当在汉克斯盐溶液中孵育时，MEHP、MnHP、MnOP和氯贝酸均可显著快速刺激肝细胞中的脂肪酸氧化和甘油三酯合成。细胞中极低密度脂蛋白（VLDL）的输出要么未改变，要么有所减少。相比之下，在从随意进食但在上午约9:30处死的大鼠分离的肝细胞中，MEHP和氯贝酸未改变脂肪酸氧化或甘油三酯合成，而MnOP和MnHP增加了甘油三酯合成但降低了脂肪酸氧化。在完全组织培养基（利博维茨L-15）中孵育细胞，禁食的影响基本消除。结果表明，MEHP及其直链类似物可以以游离酸或辅酶A酯的形式，在脂肪酸代谢的变构调节中模拟脂肪酸的作用。
