Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide.

RESULTS: Incubation in vitro of human recombinant and erythrocyte (RBC) thiopurine methyl transferase (TPMT) with furosemide, bendroflumethiazide and trichlormethiazide demonstrated inhibition of both enzyme preparations, with IC50 values of 170 microM, 360 microM and 1 mM, respectively. Kinetic studies revealed that the inhibition was mixed or non-competitive with regard both to the thiopurine substrate 6-mercaptopurine (6-MP) and the methyl donor S-adenosyl-L-methionine. CONCLUSION: Since S-methylation is a major pathway in the metabolism of thiopurines, our data point to the possibility of a clinically significant diuretic-thiopurine interaction in patients treated simultaneously with these drugs.

Nuclear deviation in hepatic parenchymal cells on sinusoidal surfaces in Arctic animals.

In normal rat and human, most of the nuclei of hepatic parenchymal cells are centrally located in the cytoplasm. However, it is reported that the nuclei of hepatic parenchymal cells are situated at a deviated position on sinusoidal surfaces under pathological situations such as chronic hepatitis, hepatocellular carcinoma, adenomatous hyperplasia, or regeneration. During a study on the mechanism of extreme vitamin A-accumulation in hepatic stellate cells of arctic animals including polar bears, arctic foxes, bearded seals, and glaucous gulls, we noticed that these arctic animals displayed the nuclear deviation in hepatic parenchymal cells on sinusoidal surfaces. In this study, we assessed the frequency of hepatic parenchymal cells showing the nuclear deviation on the sinusoidal surfaces in arctic animals. A significantly higher frequency of the nuclear deviation in hepatic parenchymal cells was seen in polar bears (89.8+/-3.4%), arctic foxes (68.6+/-10.5%), bearded seals (63.6+/-8.4%), and glaucous gulls (24.2+/-5.8%), as compared to that of control rat liver (9.8+/-3.5%). However, no pathological abnormality such as fibrosis or necrosis was observed in hepatic parenchymal and nonparenchymal cells of arctic animals, and there were no differences in the intralobular distribution of parenchymal cells displaying the nuclear deviation in the livers from either arctic animals and control rats. The hepatic sinusoidal littoral cells such as stellate cells or extracellular matrix components in the perisinusoidal spaces may influence the nuclear positioning and hence the polarity and intrinsic physiological function of parenchymal cells.