The effects of cycloheximide, actinomycin D, and ethionine on the biliary excretion of labelled alpha-naphthylisothiocyanate in rats.

It has recently been shown that rats given a mixture of [³H-4-naphthyl] α-naphthylisothiocyanate (ANIT) and [¹⁴C-isothiocyanate] ANIT having a ${}^3\text{H}{}^{14}\text{C}$ ratio equal to 6.3, excreted more ³H than ¹⁴C into bile during the first 8 hours after ANIT administration, the ratio increasing to 7.5. However, in rats pretreated with cycloheximide, the ratio remained similar to that of the ANIT mixture administered (6.3) and data indicated that this inhibitor blocked this increase in ³H. Here we present further data showing that this effect by cycloheximide is dose-dependent, can be observed as late as 16 hours after ANIT administration, and is sensitive to early posttreatment times not to exceed 1 hour after ANIT. Actinomycin D and dl-ethionine also significantly blocked the increase in ${}^3\text{H}{}^{14}\text{C}$ ratio but it was found necessary to give both inhibitors 4 hours before ANIT administration in order to effect the decrease within 8 hours after ANIT administration. If given 30 minutes before ANIT, these inhibitors showed no effect until 9 hours after ANIT administration. These data further support the conclusion that cycloheximide, as well as actinomycin D and dl-ethionine, may act by inhibiting the formation of a toxic moiety of ANIT. The effects of these inhibitors on decreasing the excretion of a ³H moiety of ANIT in bile seem to coincide, on the basis of potency and protection, with their effects against hyperbilirubinemia and cholestasis.