Sparteine oxidation polymorphism: a family study.

Abstract

1 Polymorphic oxidation of the pharmacogenetic probe drug sparteine was investigated in 35 parents and 29 siblings of 20 unrelated poor metabolizer (PM) probands. Phenotyping was carried out on the basis of metabolic ratio (MR) = sparteine/dehydrosparteines in the 12 h urine. The distribution of MR was bimodal: 47 relatives (20 siblings and 27 parents) had MR ranging from 0.22-12 and were defined as extensive metabolizers (EM) whereas MR ranged from 20-340 in nine siblings and eight parents thus defined as PM. 2 The 20 pedigrees confirmed that poor metabolism of sparteine is inherited as an autosomal recessive character.3 The mean recovery of dehydrosparteines (% of dose) was 27% in 23 positively identified drug free heterozygotes compared with 37% in unrelated EM (both genotypes) (P < 0.05) previously phenotyped. Degrees of dominance of 73% and 77% were calculated on basis of log excretion of dehydrosparteines (% of dose in 12 h urine) and log MR, respectively.

Sparteine oxidation polymorphism in Greenlanders living in Denmark.

“…The frequency of PM was 6/185 = 3.2% compared with 7.3% found in 301 Danes (Br0sen et al, 1985) (p = 8.8%, Fischer's exact test). As in the Danes (Br0sen et al, 1985(Br0sen et al, , 1986a, the sparteine test could not distinguish the two genotypes within the dominant phenotype. Comparative studies of families and populations (Evans et al, 1983;Br0sen et al, 1986a) have indicated that sparteine oxidation on the average is faster in homozygous dominants than in heterozygotes.…”

“…In Caucasians, two phenotypes are clearly separated: poor metabolizers (PM) who make up 7-9% of the population and extensive metabolizers (EM) who make up the rest (Vinks et al, 1982;Evans et al, 1983;Eichelbaum & Woolhouse, 1985;Br0sen et al, 1985). The PM phenotype is inherited as an autosomal Mendelian recessive trait, whereas the EM phenotype comprises both heterozygotes and homozygous dominants (Evans et al, 1983;Br0sen et al, 1986a).…”

A dose‐effect study of the in vivo inhibitory effect of quinidine on sparteine oxidation in man.

“…A distinct isozyme of cytochrome P450, P450dbl, catalyses the oxidation of sparteine and debrisoquine, and recent studies (Gonzalez et al, 1988;Zanger et al, 1988) have shown that P450dbl is missing in the livers of some PM. Family studies showed that PM are homozygotes for a recessive autosomal gene (Br0sen et al, 1986a;Evans et al, 1980Evans et al, , 1983. The sparteine/ debrisoquine oxidation polymorphism is a major determinant of the elimination of more than 20 drugs in current use, with implications for the clinical use of antidepressants, some neuroleptics and some antiarrythmics (Br0sen & Gram, 1989a).…”

Pharmacogenetics of drug oxidation via cytochrome P450 (CYP) in the populations of Denmark, Faroe Islands and Greenland

“…The 35 parents and 20 siblings of 20 out of the 22 poor metabolizers were also phenotyped [8] , and the pedigrees confirmed that poor metabolism is inherited in an autosomal recessive trait. In two subsequent studies also using sparteine to probe for CYP2D6 in 358, 327 and 278 healthy subjects, respectively [9 -11] ( Figure 2 ), there were 33 (9.2%), 27 (8.3%) and 28 (10.1%) poor metabolizers, respectively.…”

“…In a subsequent population study, there were only three poor metabolizers out of 327 subjects (0.92%) [8] . These figures are in keeping with other European populations [25] .…”