Bieri F, Stäubli W, Kelly S, Waechter F, Bentley P
Central Toxicology Unit, CIBA-GEIGY Ltd., Basel, Switzerland.
Mol Toxicol. 1987;1(4):439-44.
Previously, we have established that some peroxisome proliferators, a class of nongenotoxic hepatocarcinogens, are able to induce replicative DNA synthesis (RDS) in cultured hepatocytes. Hepatomegaly observed after short-term in vivo treatment correlated better with the ability to induce RDS than with the potency as peroxisome proliferator assessed in vitro. To clarify the challenging question of the limited sensitivity of primates to peroxisome proliferators, primary cultures of marmoset hepatocytes have been treated with nafenopin for some days. As expected from in vivo observations, no evidence for peroxisome proliferation could be observed. However, nafenopin induced a dose-dependent increase in the amount of RDS, but this induction was measurable only when the serum was absent from the culture medium. These results confirm that peroxisome proliferation and mitogenicity might be independent properties of peroxisome proliferators. Since in vivo the ability of compounds to induce RDS in liver cells is relevant to at least one key parameter of the hepatocarcinogenic response, it is suggested that measurement of RDS inducibility in cultured hepatocytes from different species might be relevant and useful to assess species differences in the liver tumor potency of nondirectly genotoxic compounds.
此前，我们已经证实，某些过氧化物酶体增殖剂（一类非遗传毒性肝癌致癌物）能够在培养的肝细胞中诱导复制性DNA合成（RDS）。短期体内治疗后观察到的肝肿大与诱导RDS的能力相关性更好，而与体外评估的作为过氧化物酶体增殖剂的效力相关性较差。为了阐明灵长类动物对过氧化物酶体增殖剂敏感性有限这一具有挑战性的问题，将狨猴肝细胞原代培养物用萘芬诺平处理了若干天。正如体内观察所预期的那样，未观察到过氧化物酶体增殖的证据。然而，萘芬诺平诱导了RDS量的剂量依赖性增加，但这种诱导只有在培养基中无血清时才可检测到。这些结果证实，过氧化物酶体增殖和有丝分裂原性可能是过氧化物酶体增殖剂的独立特性。由于在体内化合物诱导肝细胞中RDS的能力与肝癌致癌反应的至少一个关键参数相关，因此建议测定来自不同物种的培养肝细胞中RDS的诱导能力，可能与评估非直接遗传毒性化合物的肝肿瘤效力的物种差异相关且有用。
