Wroblewski V J, Olson J R
Toxicol Appl Pharmacol. 1985 Nov;81(2):231-40. doi: 10.1016/0041-008x(85)90159-0.
Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the rat having an LD50 about 25-fold greater than the guinea pig. The metabolism of TCDD was examined by incubating hepatocytes isolated from these animals with purified [14C]TCDD (2.2 microM) for 8 hr. Over the 8-hr incubation, cytochrome P-450 content and ethoxyresorufin O-deethylase and benzphetamine N-demethylase activities were well maintained, indicating the functional viability of the hepatocytes. Quantitative differences were observed in the rate of [14C]TCDD metabolism, with hepatocytes from control rats metabolizing TCDD at a rate 2.8-fold greater than hepatocytes from control guinea pigs. The role of the hepatic cytochrome P-450-448-dependent monooxygenase system in the metabolism of TCDD was examined through the use of hepatocytes isolated from animals pretreated with either TCDD (5 micrograms/kg, ip; 72 hr prior to hepatocyte isolation) or phenobarbital (80 mg/kg, ip X 3 days; 24 hr prior to isolation). The rate of [14C]TCDD metabolite formation in hepatocytes from TCDD pretreated guinea pigs (0.26 +/- 0.14 pmol mg cell protein-1 hr-1) was unchanged from the control rate (0.25 +/- 0.07), while the rate in hepatocytes from TCDD pretreated rats (2.26 +/- 0.43 pmol mg-1 hr-1) was 3.2-fold greater than control (0.70 +/- 0.10) and nine times greater than in hepatocytes from TCDD-pretreated guinea pigs. In addition, significant differences were observed in the profiles of the metabolites formed by hepatocytes from TCDD-pretreated rats and guinea pigs. On the other hand, phenobarbital pretreatment produced little change in the rate of [14C]TCDD metabolism in rat hepatocytes (0.98 +/- 0.13 pmol mg-1 hr-1). These results suggest that TCDD may be metabolized by a TCDD inducible form of cytochrome P-448 which is expressed in the rat but not in the guinea pig. Furthermore, the differences in the hepatic metabolism of TCDD in the rat and guinea pig and in the ability of TCDD to induce its own rate of metabolism may play a major role in explaining the varying susceptibility of these species to the acute toxicity of TCDD.
2,3,7,8-四氯二苯并对二恶英（TCDD）的急性毒性存在显著的种间差异，大鼠的半数致死剂量（LD50）比豚鼠高约25倍。通过将从这些动物分离的肝细胞与纯化的[14C]TCDD（2.2微摩尔）孵育8小时来检测TCDD的代谢。在8小时的孵育过程中，细胞色素P-450含量以及乙氧异吩唑酮O-脱乙基酶和苄非他明N-脱甲基酶活性得到良好维持，表明肝细胞具有功能活性。观察到[14C]TCDD代谢速率存在定量差异，对照大鼠的肝细胞代谢TCDD的速率比对照豚鼠的肝细胞高2.8倍。通过使用从用TCDD（5微克/千克，腹腔注射；肝细胞分离前72小时）或苯巴比妥（80毫克/千克，腹腔注射×3天；分离前24小时）预处理的动物分离的肝细胞，研究了肝脏细胞色素P-450-448依赖性单加氧酶系统在TCDD代谢中的作用。TCDD预处理的豚鼠肝细胞中[14C]TCDD代谢产物形成速率（0.26±0.14皮摩尔/毫克细胞蛋白-1小时-1）与对照速率（0.25±0.07）无变化，而TCDD预处理的大鼠肝细胞中速率（2.26±0.43皮摩尔/毫克-1小时-1）比对照（0.70±0.10）高3.2倍，比TCDD预处理的豚鼠肝细胞高9倍。此外，观察到TCDD预处理的大鼠和豚鼠肝细胞形成的代谢产物谱存在显著差异。另一方面，苯巴比妥预处理对大鼠肝细胞中[14C]TCDD代谢速率（0.98±0.13皮摩尔/毫克-1小时-1）几乎没有影响。这些结果表明，TCDD可能由细胞色素P-448的TCDD诱导形式代谢，该形式在大鼠中表达而在豚鼠中不表达。此外，大鼠和豚鼠中TCDD肝脏代谢的差异以及TCDD诱导其自身代谢速率的能力差异可能在解释这些物种对TCDD急性毒性的不同易感性中起主要作用。
