Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract

Abstract

Br J Clin Pharmacol AimThe aim of this study was to quantify the mRNA expression of three cytochromes P450 (CYP) and P-glycoprotein (P-gp) in the human gastrointestinal (GI) tract. MethodBiopsies were obtained from gastric, duodenal, colonic and rectal mucosa during routine gastro-colonoscopy in 27 patients. The biopsies were snap-frozen in liquid nitrogen. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the quantitative analyses of mRNA expressed by the CYP2E1, CYP3A4 and CYP3A5 genes, and the MDR1 gene coding for P-gp protein. The mRNA expression of b-actin was used as an internal standard for comparisons between samples. ResultsAll CYP genes were expressed at all locations throughout the GI tract, although all showed substantial interindividual variation. CYP2E1 had the highest expression at all locations ( P < 0.05 to P < 0.0001), except in the right colon. CYP3A4 and CYP3A5 had their highest mRNA expression in the duodenum ( P < 0.001 and P < 0.000 001, respectively) and CYP2E1 in the stomach ( P < 0.01). MDR1 mRNA concentrations increased along the GI tract with the highest expression being in the left colon ( P < 0.000001) . ConclusionMultiple sampling within the same individual enabled us to study the intraindividual variation in expression of CYP and MDR1 genes along the GI tract. We find that CYP2E1 mRNA expression is higher than that of the other CYPs . CYP3A expression is highest in the duodenum and that of MDR1 increases from stomach and duodenum to colon.

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

“…Initial disintegration of LCP-Tacro tablets has been shown to occur in the stomach and/or proximal small bowel but complete disintegration (and presumably optimal absorption) [41] occurs in the distal small bowel or the colon (FIGURE 2) [34]. There appears to be less gut CYP3A4 activity in the distal portions of the gastrointestinal system [42] and thus less pre-systemic metabolism of tacrolimus, resulting in lower clearance and further increased bioavailability.…”

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…In that study, we found that the magnitude of mdr1a mRNA was in the order of ileum > jejunum > duodenum, while that of CYP3A mRNA was in the opposite order; further, of cyclosporin A under physiological conditions, whereas after induction by dexamethasone induced these mRNAs more strongly in the intestinal regions where expression was weaker in untreated animals. Thorn et al [33] reported regarding the expression of CYP and mdr mRNAs along the human gastrointestinal tract. Then, the pattern of expression of these mRNAs in duodenum, jejunum and ileum of human was well similar to those of our mice.…”

Reversal in multidrug resistance by magnetic nanoparticle of Fe3O4 loaded with adriamycin and tetrandrine in K562/A02 leukemic cells

“…The conditions for PCR were as follows: 94 °C predenaturation for 5 min, 94 °C denaturation for 30 s, 56 °C annealing for 30 s, 72 °C extension for 1 min followed by 72 °C 10 min for 35 cycles. Aliquots of the PCR product were electrophoresed on 1.5% agarose gels and PCR fragments were visualized by UV illumination (UVP GDS7500 Gel, Upland, CA, USA) stained by ethidium bromide (Thörn et al 2005). The fl uorescence intensity of β-actin fragments served as the criterion for the MDR1 fragments.…”