In vivo validation and physiologically based biokinetic modeling of the inhibition of SULT-mediated estragole DNA adduct formation in the liver of male Sprague-Dawley rats by the basil flavonoid nevadensin.

摘要

Scope. The present work investigates whether the previous observation that the basil flavonoid nevadensin is able to inhibit sulfotransferase (SULT)-mediated estragole DNA adduct formation in primary rat hepatocytes could be validated in vivo. Methods and results. Estragole and nevadensin were co-administered orally to Sprague-Dawley rats, at a ratio reflecting their presence in basil. Moreover, previously developed physiologically based biokinetic (PBBK) models to study this inhibition in rat and in human liver were refined by including a submodel describing nevadensin kinetics. Nevadensin resulted in a significant 36% reduction in the levels of estragole DNA adducts formed in the liver of rats. The refined PBBK model predicts the formation of estragole DNA adducts in the liver of rat with less than twofold difference compared to in vivo data and suggests more potent inhibition in the liver of human compared to rat due to less efficient metabolism of nevadensin in human liver and intestine. Conclusion. Given the role of the SULT-mediated DNA adduct formation in the hepatocarcinogenicity of estragole, the results of the present study suggest that the likelihood of bioactivation and subsequent adverse effects in rodent bioassays may be lower when estragole is dosed with nevadensin compared to dosing of pure estragole