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An oligopeptide transporter (PEPT1) in the small intestine plays an important role in the absorption of small peptides and peptide-like drugs. We examined the effect of thyroid hormone 3,5,3'-L-triiodothyronine ([T.sub.3]) on the activity and expression of PEPT1 in human intestinal Caco-2 cells. Treatment of Caco-2 cells with [T.sub.3] inhibited [[sup.14]C]glycylsarcosine uptake in a time- and dose-dependent manner. [sup.14]C]glycylsarcosine uptake was reduced by pretreatment of the cells with 100 nM [T.sub.3] for 4 days (67% of control value), whereas methyl-[alpha]-D-[U-[sup.14]C]glucopyranoside and [[sup.3]H]threonine uptake were not decreased. Kinetic analysis showed that [T.sub.3] treatment significantly decreased the maximum uptake ([V.sub.max]) value for [[sup.14]C]glycylsarcosine uptake but had no effect on the [K.sub.m] value. Moreover, [T.sub.3] treatment caused a significant decrease in the amount of PEPT1 mRNA (25% of the control). Western blotting indicated that the amount of PEPT1 protein in the apical membrane was decreased (70% of the control). These findings indicate that [T.sub.3] treatment inhibits the uptake of [[sup.14]C]glycylsarcosine by decreasing the transcription and/or stability of PEPT1 mRNA. intestinal absorption; intestinal oligopeptide transporter; hormonal regulation; gene expression

Mizuuchi, Hiroshi, Toshiya Katsura, Kayoko Ashida, Yukiya Hashimoto, and Ken-ichi Inui. Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells. Am J Physiol Gastrointest Liver Physiol 278: G563-G569, 2000.--Substrate specificity and pH dependence of the transport system for diphenhydramine were investigated in Caco-2 cell monolayers. Diphenhydramine uptake was not affected by any typical substrate for the renal organic cation transport system except procainamide. Along with procainamide, tertiary amine compounds with N-dimethyl or N-diethyl moieties in their structures inhibited the diphenhydramine uptake. Moreover, accumulation of diphenhydramine was stimulated by preloading the Caco-2 cells with these tertiary amines (trans-stimulation effect), indicating the existence of the specific transport system for tertiary amines with N-dimethyl or N-diethyl moieties. Efflux of diphenhydramine from monolayers was enhanced by medium acidification. In addition, intracellular acidification resulted in marked stimulation of diphenhydramine accumulation. ATP depletion of the cells caused an enhancement of diphenhydramine accumulation, suggesting the involvement of an active secretory pathway. However, P-glycoprotein did not mediate the diphenhydramine transport. These findings indicate that a novel pH-dependent tertiary amine transport system that recognizes N-dimethyl or N-diethyl moieties is involved in diphenhydramine transport in Caco-2 cells. organic cation; intestinal absorption; intestinal secretion; hydrogen/organic cation antiport system