Hissink A M, Van Ommen B, Krüse J, Van Bladeren P J
Toxicology Division, TNO Nutrition and Food Research Institute, Zeist, The Netherlands.
Toxicol Appl Pharmacol. 1997 Aug;145(2):301-10. doi: 10.1006/taap.1997.8184.
A physiologically based pharmacokinetic (PB-PK) model was developed for 1,2-dichlorobenzene (1,2-DCB) for the rat. This model was adjusted for the human situation, using human in vitro parameters, including a Vmax and Km determined with human microsomes. For comparison, the Vmax and Km values from the rat were scaled allometrically to the human case. The model was used in two ways: (1) Acute hepatotoxicity was related to the amount of reactive metabolites (epoxides) formed in vitro. For rats, the hepatic concentration of epoxide metabolites in vivo after exposure to a toxic dose level (250 mg/kg bw) was predicted using in vitro parameters. For man, the dose level needed to obtain the same toxic liver concentration of reactive metabolites as in rat was predicted, assuming a concentration-effect relationship in the liver. It could be concluded that this concentration is not reached, even after induction of the oxidation step, due to saturation of metabolism and a concomitant accumulation of 1,2-DCB in fat. (2) Hepatotoxicity was related to depletion of glutathione (GSH) in the liver. In the model, the consumption of hepatic GSH by metabolism (based on in vivo and in vitro data) and normal turnover was described. In vivo validation was conducted by comparing the predictions of the model with the results of a GSH depletion study performed at two dose levels (50 and 250 mg/kg bw). Subsequently, the GSH consumption by 1,2-DCB metabolites was estimated for man using human in vitro metabolic data. GSH turnover in human liver was assumed to be the same as that in rat. It appeared that at a dose level of 250 mg/kg, hepatic GSH was completely depleted after 10 hr for man, whereas for the rat a maximum depletion of 75% was predicted, after 15 hr. The presented model provides a quantitative tool for evaluating human risk for two different toxicity scenarios, namely covalent binding of reactive metabolites and depletion of GSH.
已为大鼠建立了基于生理的1,2-二氯苯（1,2-DCB）药代动力学（PB-PK）模型。该模型根据人体情况进行了调整，使用了人体体外参数，包括用人微粒体测定的Vmax和Km。为作比较，将大鼠的Vmax和Km值按异速生长比例换算至人体情况。该模型有两种用途：（1）急性肝毒性与体外形成的反应性代谢物（环氧化物）的量相关。对于大鼠，使用体外参数预测暴露于毒性剂量水平（250 mg/kg体重）后体内环氧化物代谢物的肝脏浓度。对于人类，假设肝脏中存在浓度-效应关系，预测获得与大鼠相同毒性肝脏浓度的反应性代谢物所需的剂量水平。可以得出结论，由于代谢饱和以及1,2-DCB在脂肪中的伴随蓄积，即使在诱导氧化步骤后，该浓度也无法达到。（2）肝毒性与肝脏中谷胱甘肽（GSH）的消耗相关。在模型中，描述了代谢（基于体内和体外数据）和正常周转对肝脏GSH的消耗。通过将模型预测结果与在两个剂量水平（50和250 mg/kg体重）进行的GSH消耗研究结果进行比较，进行了体内验证。随后，使用人体体外代谢数据估算人体中1,2-DCB代谢物对GSH的消耗。假设人体肝脏中GSH的周转与大鼠相同。结果显示，在250 mg/kg的剂量水平下，人体肝脏中的GSH在10小时后完全耗尽，而对于大鼠，预测在15小时后最大消耗75%。所提出的模型为评估两种不同毒性情况（即反应性代谢物的共价结合和GSH的消耗）下的人体风险提供了一种定量工具。
