Therapeutic
reactivation of the γ-globin genes for fetal
hemoglobin (HbF) production is an attractive strategy for treating
β-thalassemia and sickle cell disease. It was reported that
genetic knockdown of the histone lysine methyltransferase EHMT2/1
(G9a/GLP) is sufficient to induce HbF production. The aim of the present
work was to acquire a G9a/GLP inhibitor that induces HbF production
sufficiently. It was revealed that tetrahydroazepine has versatility
as a side chain in various skeletons. We ultimately obtained a promising
aminoindole derivative (DS79932728), a potent and orally bioavailable
G9a/GLP inhibitor that was found to induce γ-globin production
in a phlebotomized cynomolgus monkey model. This work could facilitate
the development of effective new approaches for treating β-thalassemia
and sickle cell disease.
5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p.o.) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real-time PCR and Western blotting, respectively. In the 5-FU-treated rats, the protein levels of P-gp and Bcrp in the upper segment were significantly increased to 15- and 2.6-fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5-FU in almost all segments. A remarkable increase in P-gp expression was shown, the uptake of digoxin, a P-gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5-FU-treated rats was decreased compared with that of the control. In conclusion, 5-FU-induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5-FU-induced intestinal damage may affect transporter-mediated drug absorption of orally administered drugs in the clinical setting.
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