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.

Thiopurine S-methyltransferase (TPMT) activity exhibits genetic polymorphism. The purpose of this investigation was to identify TPMT mutant alleles in the Saami population as a basis of developing genotyping tests for prediction of TPMT activity. The most predominant allele in Saamis (n = 194) was the TPMT*3C allele (A719G mutation) representing 92% of the mutant alleles, with an estimated allelic frequency of 3.3%. The most frequent allele in Caucasians (n = 66) living in the same geographic area was the TPMT*3A (A719G and G460A mutations) representing 91% of the mutant alleles, with an estimated allelic frequency of 3.4%. A test for one mutation, A719G, may prospectively identify more than 90% of the Saami individuals who require reduction in thiopurine dose to avoid hematopoietic toxicity. In a Norwegian population, comprising both the major Caucasian population and a minor Saami population, the same genotyping tests (eg, tests for the A719G and G460A mutations) may be used.

Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes the S-methylation of the cytotoxic drugs 6-mercaptopurine and azathioprine. Red blood cell (RBC) TPMT activity is subject to genetic polymorphism, and we have previously demonstrated an interethnic difference in TPMT activity. To investigate whether there was a race-related difference in RBC TPMT activity, TPMT was measured in a Korean population sample of 309 healthy children. Mean TPMT activity in healthy Korean children was 12.4 +/- 2.4 units/ml RBC, which is similar to the earlier reported TPMT activities in white populations. In contrast to the bimodal or trimodal frequency distributions of RBC TPMT activity in most other population samples, the frequency distribution histogram, the probit plot, and the Shapiro-Wilk test supported a normal distribution of TPMT activity in this Korean population sample of healthy children. Mean RBC TPMT activity showed a tendency to decrease with age, but it was not statistically significant. No gender-related difference in RBC TPMT activity was found.

Elevated intracellular levels of cyclic guanosine monophosphate (cGMP) may induce apoptosis, and at least some cancer cells seem to escape this effect by increased efflux of cGMP, as clinical studies have shown that extracellular cGMP levels are elevated in various types of cancer. The human ATP binding cassette (ABC) transporter ABCC5 transports cGMP out of cells, and inhibition of ABCC5 may have cytotoxic effects. Sildenafil inhibits cGMP efflux by binding to ABCC5, and in order to search for potential novel ABCC5 inhibitors, we have identified sildenafil derivates using structural and computational guidance and tested them for the cGMP efflux effect. Eleven compounds from virtual ligand screening (VLS) were tested in vitro, using inside-out vesicles (IOV), for inhibition of cGMP efflux. 7 of 11 compounds predicted by VLS to bind to ABCC5 were more potent than sildenafil, and the two most potent showed Ki-values of 50 #x02013;100 nM.