Effect Of Plasma Serotonin On The Expression Of Transporters And Metabolic Enzymes In The Liver And Kidney Of Rats

AimsTransporters and metabolic enzymes play important roles in regulating pharmacokinetic profile of many drugs in vivo. The expression and/or function of transporters and metabolic enzymes may be alterated under certain disease conditions, and thus influence the intracorporal process of many drugs. The aim of this work was to investigate the expression of transporters and metabolic enzymes in liver and kidney of post-infectious irritable bowel syndrome (PI-IBS) rats, specific drugs were also applied to alter the plasma 5-HT level in rats in order to further clarify the effect of plasma 5-HT level on the expression of transporters and metabolic enzymes in liver and kidney, and the underlying mechanism was further investigated.MethodsPI-IBS rat model was developed by rectal administration of TNBS solution. Intestinal enterochromaffin (EC) cell number and plasma 5-HT level of rats were evaluated by immunohistochemistry technique and LC/MS/MS analysis, respectively. The expression of multidrug resistance-associated protein 2 (Mrp2) and Na+/taurocholate co-transporting polypeptide (NTCP) in rats were evaluated by Western-blot technique. Moreover,5-HT precursor 5-hydroxytryptophan (5-HTP) and 5-HT depleting agent parachlorophenylalanine (pCPA) were applied to alter plasma 5-HT level to further clarify the effect of plasma 5-HT level on the expression of liver transporters (Mrp2, NTCP, P-gp), metabolic enzymes (CYP3A4, CYP2D6 and nuclear receptors (PXR, CAR, FXR). The effect of plasma 5-HT level on the expression of renal transporters (OAT1,OAT3, OCT2) as well as the function of OCT2 were also tested by Western blot technique and cumulative excretion test in rats, respectively.Results1. Colonic EC cell density and plasma 5-HT level were all significantly increased in TNBS-induced PI-IBS rats when compared to that of the normal rats, suggesting the occurrence of colonic EC cell hyperplasia and high plasma 5-HT level in PI-IBS rats. In PI-IBS rats, the expression of Mrp2 was significantly decreased when compared to that of the control, indicating that higher plasma 5-HT level may be involved in regulating the expression of hepatic transporters.2. Compared to the normal rats,5-HTP treatment significantly increased 5-HT level and decreased hepatic expression of Mrp2 as well as P-Glycoprotein (P-gp); while pCPAtreatment significantly decreased the plasma 5-HT level and increased the expression of Mrp2 and P-gp. These results indicated that plasma 5-HT level had effect on regulating the expression of Mrp2 and P-gp. Moreover, our results also found that plasma 5-HT level had little effect on the expression of metabolic enzyme CYP3A4 and CYP2D6 in liver.3. Plasma 5-HT level had effect on the expression of CAR, i.e. high plasma 5-HT level down-regulated CAR expression, while low plasma 5-HT level up-regulated CAR expression. However, plasma 5-HT level had little effect on the expression of PXR and FXR4. Plasma 5-HT level had little effect on the expression of OCT2, OAT1 and OAT3 in renal; also had no effect on the function of OCT2.ConclusionsThe results from this study show that the colonic EC cell density and plasma 5-HT level is markedly increased in TNBS-induced PI-IBS rats, high plasma 5-HT level down-regulate the expression of Mrp2 and P-gp, and the expression of nuclear receptor CAR may contribute to the regulatory effect of plasma 5-HT level on hepatic transporters expression. Results from this study may provide potential evidence for clinical estimating the pharmacokinetic feature and medication safety when drugs are administered in PI-IBS patients.