4th Annual Pharmacogenomics and Medicine Lectures.

In the future, pharmacogenomics will play an important role in the treatment of patients by making it possible to predict drug response based on an individual's genetic make-up. Similarly, pharmacogenomics may be used to reduce the probability that adverse effects will occur. The use of a patient's genetic information will lead to greater predictability in clinical outcomes and personalisation of medical care. Pharmacogenomic information can also aid in drug development by helping to select individuals that are likely to respond to a medication for participation in clinical trials. Integration of pharmacogenomics into the healthcare system has a number of potential economic benefits, including reduced costs of healthcare and drug discovery. The FDA has no specific plans to regulate therapy-guiding pharmacogenomic tests, which are different from diagnostic genetic tests. There are a number of ethical issues related to pharmacogenomics, including the credibility of the system for protecting the rights and welfare of human research subjects, general concerns about genetic research, privacy issues and equitable distribution of the technology. To ensure integration of pharmacogenomics into the healthcare system it will be important to obtain public support through education about the benefits and risks of this technology.

Sulphasalazine fails to prevent development of mucosal ulceration and 5-lipoxygenase activity in guinea-pigs with chronic inflammatory bowel disease induced by combined bacterial immunization and oral carrageenin.

A model of inflammatory bowel disease in guinea-pigs involving a 14 day initial treatment with formalin-killed Bacteroides vulgatus subcutaneously and oral carrageenin plus live B. vulgatus for 10 days was used to determine the effects of sulphasalazine 100 mg kg-1 day-1 b.i.d., p.o. given for 4, 7 and 10 days after cessation of the bacterial/carrageenin treatment on the morphological and histological states of the established disease and on the production of the principal 5-lipoxygenase products, 5-hydroxyeicosatetraenoic acid and leukotriene B4. The drug treatment did not cause any significant changes in this established disease as measured by these parameters.

Inflammatory bowel disease induced by combined bacterial immunization and oral carrageenan in guinea pigs. Model development, histopathology, and effects of sulfasalazine.

A model of experimentally induced inflammatory bowel disease (IBD) featuring colitis, originally devised by Onderdonk and co-workers in guinea pigs, was modified to establish the optimal conditions for ulcer development. Upon varying the time of subcutaneous immunization with Bacteroides vulgatus and concomitant oral administration of acid-degraded iota-carrageenan and viable B. vulgatus, it was found that the optimal times of administering these agents were one to two weeks and five to six days, respectively. Light microscopy of the colon and cecum of the guinea pigs given the optimized treatment for ulcer induction revealed pronounced edema, inflammation, and lesions of the mucosa. Transmission electron microscopy of the mucosa from these animals showed the presence of large numbers of leukocytes in the subepithelial region, the majority being polymorphonuclear neutrophils which possessed large electron-dense granules or rods. Oral administration of 300 mg/kg/day sulfasalazine (salicylazosulfapyridine) for 14 days to guinea pigs given the optimized treatment for ulcer induction failed to reduce the numbers of ulcers or the histopathology gradings and fine structural changes of the mucosal inflammatory changes, but did reduce the symptoms of diarrhea.

Zinc uptake by basolateral membrane vesicles from rat small intestine.

Zinc uptake (transport and binding) by basolateral membrane vesicles was investigated using membranes derived from small intestines of rats fed zinc-adequate and zinc-deficient diets. Uptake was separated into saturable and nonsaturable (diffusion) components. Kinetic analysis of initial rates of the saturable component of uptake (at 1 min) indicates half maximal uptake (Km) by vesicles from zinc-adequate rats was observed at a medium Zn2+ concentration of 24 microM. The maximum Zn2+ uptake rate (Jmax) of the saturable component was 17 nmol/(mg protein.min). Dietary zinc intake did not affect these parameters. Zn2+ transport by the basolateral membrane may involve an ATP-driven mechanism.

Copper and zinc absorption in the rat: mechanism of mutual antagonism.

The influence that copper and zinc exert on each other's absorption was studied by using the isolated, vascularly perfused rat-intestine system. In the first series of experiments, rats were fed for 1 wk one of nine diets, with different copper and zinc concentrations representing low, adequate and high dietary metal intakes. Copper concentrations were 1, 6 and 36 mg/kg diet and zinc concentrations were 5, 30 and 180 mg/kg. The small intestine was perfused with M199 tissue culture medium containing 6 mg/L copper and 30 mg/L zinc. Neither metal was found to significantly alter the other's absorption. High dietary zinc increased metallothionein-bound copper but did not change the intracellular copper concentration. In the second series of experiments, the dietary copper and zinc concentrations were held at 6 mg/kg and 30 mg/kg, respectively, while the metal concentrations in the luminal perfusate were changed (from 1 to 36 mg/L and from 5 to 180 mg/L for copper and zinc, respectively). The higher copper concentrations in the perfusate increased zinc accumulation in mucosal cells and decreased the zinc transferred to the portal perfusate at the highest luminal zinc concentration. These data indicate that a competition and/or inhibition of a pathway for zinc out of the mucosal cell occurs at high luminal copper concentrations. High luminal zinc concentrations in the perfusate decreased the copper concentration in the mucosal cell cytosol and the amount transferred to the portal effluent. These results taken together indicate that a competition and/or inhibition of copper or zinc intake into intestinal cells occurs when the luminal concentration of the respective congener is very high.

Influence of intraluminal constituents on zinc absorption by isolated, vascularly perfused rat intestine.

An isolated, vascularly perfused rat intestine system was utilized to compare the influence of a variety of potential zinc-binding compounds on zinc absorption. Citric acid, cysteine, reduced glutathione, histidine, methionine, picolinic acid and tryptophan were added to the lumen perfusate at 110 microM. Two lumen perfusate pH values (4.2 and 6.6) were compared. The influence of EDTA at pH 6.6 was also investigated as was the influence of citric acid, histidine, picolinic acid and tryptophan additions to the lumen perfusate at 550 microM. Of the substances tested only EDTA significantly enhanced the transfer of zinc from the lumen to the portal circulation. These results suggest these potential zinc chelators, exclusive of EDTA, do not promote zinc absorption by the intestine in this system.