Shaw David, Lee Rebecca, Roberts Ruth A
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK.
Arch Toxicol. 2002 Jun;76(5-6):344-50. doi: 10.1007/s00204-002-0342-x. Epub 2002 Apr 19.
Diisononylphthalate (DINP) is one of the group of dialkyl phthalate esters used widely to impart flexibility to polyvinyl chloride (PVC) products. However, DINP and other phthalates are rodent peroxisome proliferators (PPs), a class of compounds that cause rodent hepatic peroxisome proliferation, induction of DNA synthesis and suppression of apoptosis leading to liver tumours. Despite these adverse effects in rodent liver, humans appear to be nonresponsive to the adverse effects of PPs. Here, we have examined species differences in the response of rat and human hepatocytes to MINP, a principle metabolite of DINP and the proximal peroxisome proliferator. In rat hepatocytes in vitro, MINP caused a concentration-dependent induction of peroxisomal beta-oxidation. Similarly, MINP caused a concentration-dependent suppression of apoptosis and induction of DNA synthesis. In contrast to the pleiotropic response noted in rat hepatocytes, MINP did not cause induction of beta-oxidation, stimulation of DNA synthesis or suppression of apoptosis in human hepatocytes. These data provide evidence for species differences in the hepatic response to the phthalate ester DINP, confirming that human hepatocytes are refractory to the adverse effects noted in rodents.
邻苯二甲酸二异壬酯（DINP）是一类广泛用于赋予聚氯乙烯（PVC）产品柔韧性的邻苯二甲酸二烷基酯。然而，DINP和其他邻苯二甲酸盐是啮齿动物过氧化物酶体增殖剂（PPs），这类化合物会导致啮齿动物肝脏过氧化物酶体增殖、诱导DNA合成并抑制细胞凋亡，进而引发肝肿瘤。尽管对啮齿动物肝脏有这些不良影响，但人类似乎对PPs的不良影响没有反应。在此，我们研究了大鼠和人类肝细胞对DINP的主要代谢产物MINP（一种近端过氧化物酶体增殖剂）反应的种属差异。在体外培养的大鼠肝细胞中，MINP引起了过氧化物酶体β-氧化的浓度依赖性诱导。同样，MINP导致了细胞凋亡的浓度依赖性抑制和DNA合成的诱导。与在大鼠肝细胞中观察到的多效性反应相反，MINP在人类肝细胞中并未引起β-氧化的诱导、DNA合成的刺激或细胞凋亡的抑制。这些数据为肝脏对邻苯二甲酸酯DINP反应的种属差异提供了证据，证实人类肝细胞对啮齿动物中观察到的不良影响具有抗性。
