allopurinol and Methemoglobinemia

I have presented some diverse case reports which illustrate several variations on the theme of this conference. A study of caffeine metabolites revealed two kinds of interethnic variation, one pertaining to the well-known acetylation polymorphism affecting the secondary metabolism of the parent drug; the other consisted of a difference in paraxanthine excretion which might indicate an ethnic difference in renal function. Older data on the pharmacokinetics of the antihistaminic drug diphenhydramine also suggested interethnic variables in the fate of the drug which do not necessarily involve metabolizing capacity. In short, pharmacokinetic factors other than metabolism may make additional contributions to ethnic differences in drug response. Studies of taste and smell are not only models of receptor variability but they may be used to reveal underlying biochemical differences. Furthermore, a polymorphism in tasting ability constituted an epidemiological risk factor for thyroid disease which was greatly enhanced in the presence of an appropriate human leukocyte antigen (HLA, histocompatibility gene). It is clear that the HLA complex will have to be increasingly considered in relation to pharmacological responses. Variabilities of superoxide dismutase and of various enzymes involved in heme production were described briefly because of their inherent or historical interest. In each case, however, the occurrence of variants was confined to small population groups as an expression of founder effects and regional polymorphism. Several other instances of ethnic differences in drug response were merely cited.

Topics: Acetylation; Caffeine; Cytochrome P-450 Enzyme System; Diphenhydramine; Drug-Related Side Effects and Adverse Reactions; Gene Frequency; Genetic Markers; Humans; Kinetics; Methemoglobinemia; Mutagens; Phenylthiourea; Polymorphism, Genetic; Porphyrias; Racial Groups; Superoxide Dismutase; Taste; Xanthine Oxidase

Although the molecular basis of ischaemic damage of the brain is as yet unknown, it has been postulated that the uncontrolled production of reactive oxygenated species derived from molecular oxygen (including hydroxyl radicals, superoxide radicals and singlet oxygen) may play a major role in the production of such injury. The ability of various barbiturates to modify the nature and extent of membrane damage produced by various oxygen radicals generated under well-defined conditions in vitro has been directly examined using the human erythrocyte as model membrane system. Our results indicate that barbiturates are unlikely to exert their protective effects by directly scavenging singlet oxygen, superoxide or hydroxyl radicals. The highly lipophilic barbiturate thiopentone is capable of decreasing the susceptibility of membranes to oxidative degradation by a direct membrane action, a property shared by amphipathic membrane stabilizers such as propranolol. The barbiturates were found to stabilize the haeme moiety of haemoglobin preventing its conversion to methaemoglobin in the presence of hydrogen peroxide. It is postulated that a major aspect of barbiturate action in decreasing ischaemic injury to the brain may involve the stabilization of haeme-coordinated iron complexes, thereby preventing the participation of these ubiquitous substances in initiating and potentiating free radical-mediated processes which have been implicated in the production of such injury.

Topics: Barbiturates; Brain; Brain Ischemia; Chemical Phenomena; Chemistry; Erythrocytes; Free Radicals; Humans; Membranes, Artificial; Methemoglobinemia; Nitrates; Oxygen Consumption; Peroxides; Photolysis; Xanthine Oxidase