Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.
OBJECTIVE
To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil).


METHODS
Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP).


RESULTS
Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01).


CONCLUSIONS
Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.
Herrlin
K
K
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Massele
A Y
AY
Jande
M
M
Alm
C
C
Tybring
G
G
Abdi
Y A
YA
Wennerholm
A
A
Johansson
I
I
Dahl
M L
ML
Bertilsson
L
L
Gustafsson
L L
LL
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000378:metabolism*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D044383:Black People / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000008:administration & dosage / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D009853:Omeprazole / Q000008:administration & dosage / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D012016:Reference Values; D013636:Tanzania
D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; D017931:DNA Primers; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin