Bogaards J J, Freidig A P, van Bladeren P J
TNO Nutrition and Food Research, Toxicology Division, PO Box 360, 3700 AJ Zeist, The Netherlands.
Chem Biol Interact. 2001 Dec 21;138(3):247-65. doi: 10.1016/s0009-2797(01)00276-9.
The present study was designed to explain the differences in isoprene toxicity between mouse and rat based on the liver concentrations of the assumed toxic metabolite isoprene diepoxide. In addition, extrapolation to the human situation was attempted. For this purpose, enzyme kinetic parameters K(m) and V(max) were determined in vitro in mouse, rat and human liver microsomes/cytosol for the cytochrome P450-mediated formation of isoprene mono- and diepoxides, epoxide hydrolase mediated hydrolysis of isoprene mono- and diepoxides, and the glutathione S-transferases mediated conjugation of isoprene monoepoxides. Subsequently, the kinetic parameters were incorporated into a physiologically-based pharmacokinetic model, and species differences regarding isoprene diepoxide levels were forecasted. Almost similar isoprene diepoxide liver and lung concentrations were predicted in mouse and rat, while predicted levels in humans were about 20-fold lower. However, when interindividual variation in enzyme activity was introduced in the human model, the levels of isoprene diepoxide changed considerably. It was forecasted that in individuals having both an extensive oxidation by cytochrome P450 and a low detoxification by epoxide hydrolase, isoprene diepoxide concentrations in the liver increased to similar concentrations as predicted for the mouse. However, the interpretation of the latter finding for human risk assessment is ambiguous since species differences between mouse and rat regarding isoprene toxicity could not be explained by the predicted isoprene diepoxide concentrations. We assume that other metabolites than isoprene diepoxide or different carcinogenic response might play a key role in determining the extent of isoprene toxicity. In order to confirm this, in vivo experiments are required in which isoprene epoxide concentrations will be established in rats and mice.
本研究旨在根据假定的有毒代谢物异戊二烯二环氧物在肝脏中的浓度，解释小鼠和大鼠之间异戊二烯毒性的差异。此外，还尝试外推至人类情况。为此，在体外测定了小鼠、大鼠和人肝脏微粒体/胞质溶胶中细胞色素P450介导的异戊二烯单环氧物和二环氧物形成、环氧水解酶介导的异戊二烯单环氧物和二环氧物水解以及谷胱甘肽S-转移酶介导的异戊二烯单环氧物结合的酶动力学参数K(m)和V(max)。随后，将动力学参数纳入基于生理学的药代动力学模型，并预测了异戊二烯二环氧物水平的种属差异。预测小鼠和大鼠肝脏和肺中异戊二烯二环氧物的浓度几乎相似，而预测的人类水平则低约20倍。然而，当在人类模型中引入酶活性的个体间差异时，异戊二烯二环氧物的水平发生了相当大的变化。预测在细胞色素P450广泛氧化且环氧水解酶解毒能力低的个体中，肝脏中异戊二烯二环氧物的浓度会增加到与预测的小鼠浓度相似的水平。然而，由于预测的异戊二烯二环氧物浓度无法解释小鼠和大鼠在异戊二烯毒性方面的种属差异，因此后者对人类风险评估的解释并不明确。我们假设除异戊二烯二环氧物之外的其他代谢物或不同的致癌反应可能在决定异戊二烯毒性程度方面起关键作用。为了证实这一点，需要进行体内实验，在大鼠和小鼠中测定异戊二烯环氧物的浓度。
