Uptake-toxicity relationships of a series of N-substituted N'-(4-imidazole-ethyl)thiourea in precision-cut rat liver slices

R.C.A. Onderwater, J.N.M. Commandeur, M. Rooseboom, N.P.E. Vermeulen

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

A previous study showed that the cytotoxicity of a series of N-p-phenyl-substituted N′-(4-imidazole-ethyl)thiourea in precision-cut rat liver slices increased with increasing electron-withdrawing capacity of the p-substituent and may be related to the Vmax/Km values of bioactivation of the thiourea-moiety by hepatic flavin-containing monooxygenases (FMOs). However, differences in the uptake of xenobiotics into precision-cut liver slices can also have consequences for the rates of metabolism of xenobiotics. In the present study, therefore, we investigated the rate and nature of uptake of 9 N-substituted N′-(4-imidazole-ethyl)thiourea into precision-cut rat liver slices. It was found that a five-fold difference exists among a series of N-substituted N′-(4-imidazole-ethyl)thiourea both in the initial rate of uptake and in the steady-state levels ultimately achieved in the precision-cut rat liver slices. It appeared that the most cytotoxic compounds were also the most readily absorbed compounds. The concentration-dependent initial rate of uptake could be described by a carrier-mediated saturable component and a non-saturable component. At cytotoxic concentrations, the non-saturable component accounted for more than 95% of the total uptake. From this study, it is concluded that differences in rate of uptake of thiourea-containing compounds may be a contributing factor to the differences in bioactivation by FMOs as the basis of the structure–toxicity relationships observed in precision-cut rat liver slices.
Original languageEnglish
Pages (from-to)391-404
Number of pages14
JournalXenobiotica
Volume35
Issue number4
DOIs
Publication statusPublished - Apr 2005

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