Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians

Abstract

The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.

Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population.

“…Woolhouse et al (1985). This contention is supported by the observation that: (1) a PM of metoprolol was also the only PM of debrisoquine and of sparteine; (2) none of the EMs of metoprolol was misclassified by the phenotyping tests with debrisoquine and sparteine; and (3) the MRs derived from three test probes were highly significantly (P < 0.001) correlated among each other (Figure 2).…”

“…This study was motivated by that of Woolhouse et al (1985), which was conducted in a Ghanaian population in a three-way crossover manner. Woolhouse et al (1985).…”

Evidence for polymorphic oxidation of sparteine in Japanese subjects.

“…The apparent difference in the incidence of the PM phenotype for debrisoquine and sparteine may have resulted from either the very low incidence and consequently small sample sizes studied or dissociation of co-regulatory control in Japanese subjects. However, by considering the present observation coupled with that of Nakamura et al (1985), the possibility that Japanese might be a population showing a dissociation in the genetic control of debrisoquine/sparteine oxidation as indicated in a Ghanaian population study by Woolhouse et al (1985) cannot be denied. Obviously, a crossover study on debrisoquine and sparteine metabolism in an extended Japanese population is required in order to prove or reject this hypothesis and such a study is currently underway.…”

Uses and misuses of definitions of genetic polymorphism. A perspective from population pharmacogenetics [letter]

“…Inversely, if the number of poor metabolizers is below 1-2%, polymorphism is said not to be evident or its absence could have been implied (Arias et al, 1986; Correspondence: Professor T. D. Arias, Apartado 10767, Estafeta Universitaria, Panama, Republica de Panama. Iyun et al, 1986;Lou et al, 1987;Nakamura et al, 1985;Tucker et al, 1986;Woolhouse et al, 1985). This view is shared by all researchers in population pharmacogenetics who have claimed absence of evidence for the existence of polymorphism, and, presumably, by the editors and most of the reviewers of their publications.…”