Uptake-toxicity relationships of a series of N-substituted N'-(4-imidazole-ethyl)thiourea in precision-cut rat liver slices.
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.
Onderwater
R C A
RC
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Molecular Toxicology, Vrije Universiteit, Amsterdam, the Netherlands.
Commandeur
J N M
JN
Rooseboom
M
M
Vermeulen
N P E
NP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism*; D008297:Male; D042282:Microdissection; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000633:toxicity*
D013890:Thiourea