allopurinol and Porphyrias

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

The effects of acute carbamazepine (CBZ) administration on haem metabolism in rat liver were examined in relation to the mechanism by which it exacerbates hepatic porphyrias. In a screening test for drug exacerbation of porphyria developed in this laboratory, CBZ at a very small dose (1.5 mg/kg, p.o.) behaved as an exacerbator, potentiating the loss of haem utilized by tryptophan pyrrolase (TP; tryptophan 2,3-dioxygenase; L-tryptophan-O2 oxido-reductase, decyclizing; EC 1.13.11.11) and the associated induction of activity of the rate-limiting enzyme of haem biosynthesis, 5-aminolaevulinate synthase (5-ALA-S) caused by the experimental porphyrogen 3,5-diethoxycarbonyl-1,4-dihydrocollidine. A larger dose of CBZ (50 mg/kg, i.p.) induced 5-ALA-S activity by 40-100% at 3 hr. This induction was preceded by an increase in the haem saturation of TP, and was abolished when such an increase was prevented by allopurinol. 5-ALA-S induction by CBZ was not associated with decreased turnover of the enzyme, nor with any significant changes in concentration of the major hepatic haemoprotein, cytochrome P450. It is suggested that CBZ may exacerbate the hepatic porphyrias by inducing 5-ALA-S activity secondarily to an increased utilization of haem by TP.

Topics: 5-Aminolevulinate Synthetase; Allopurinol; Animals; Carbamazepine; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Enzyme Induction; Heme; Indoleamine-Pyrrole 2,3,-Dioxygenase; Liver; Male; Porphyrias; Rats; Rats, Inbred Strains; Tryptophan Oxygenase

Male C57Bl/10 mice were chronically fed hexachlorobenzene (HCB) (0.02% of the diet) alone or in combination with a single subcutaneous dose of iron (12.5 mg iron per mouse). After eight weeks the group of mice pretreated with the iron overload was highly sensitized to the porphyrogenic effect of HCB, as shown by liver porphyrin accumulation. A synergistic effect of iron was evident on other parameters too, such as HCB-induced hepatic damage, activation of type O of xanthine oxidase, and decreased activity of copper zinc superoxide dismutase and glutathione peroxidase(s). None of these parameters was affected by iron alone. Iron alone and in association with HCB markedly raised the level of lipid peroxides, the increase in the HCB group being smaller. The combined treatment resulted in a significant reduction of HCB's inductive effects on microsomal heme and cytochromes P-450 and b5 and on the activity of aryl hydrocarbon hydroxylase. The content of nonprotein sulfhydryl groups was reduced to the same extent in mice treated with HCB or HCB plus iron. The results suggest that reactive intermediates such as are formed by lipid peroxidation are not sufficient on their own to create the conditions for uroporphyrinogen decarboxylase impairment, as evident in the group of mice receiving iron overload alone. Conversely, HCB administration induced a specific condition of imbalance in the liver between formation and inactivation of reactive intermediates which was associated with hepatic porphyrin accumulation and was potentiated by concomitant administration of iron.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chlorobenzenes; Free Radicals; Hexachlorobenzene; Iron; Lipid Peroxides; Liver; Male; Mice; Mice, Inbred C57BL; Porphyrias; Porphyrins; Xanthine Oxidase

Iron kinetics, absorption and storage were studied by means of 59Fe and deferoxamine (Desferal-Ciba) in eight patients with porphyria cutanea tarda at the time of clinical activity and after allopurinol treatment. At the time of clinical manifestations, a significant impairment of erythrocyte-iron turnover and of radio-iron utilization was demonstrable in a half of the patients and a significant increase in iron absorption and turnover in patients out of 8. The measurements of surface activity in vivo showed a significant increase in storage iron. This was confirmed by the excessive urinary excretion of deferoxamine-iron, attaining three- to four-fold figures of the normal values (251 +/- 85 mg). The increased absorption of iron coupled with an abnormal porphyrin metabolism is suggestive of a double genetic defect. As a result of allopurinol treatment, normalization of iron kinetics and a moderate decrease in iron storage were demonstrable. The abnormal excretion of uroporphyrin and coproporphyrin were also brought under control. The success of treatment is attributed to the inhibitory effect of allopurinol on xanthine oxidase.

Topics: Adult; Allopurinol; Bone Marrow; Coproporphyrins; Erythrocytes; Humans; Iron; Liver; Male; Middle Aged; Plasma; Porphyrias; Spleen; Uroporphyrins