Showing papers by "Leif Bertilsson published in 1993"

Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine

Abstract: Deficient hydroxylation of debrisoquine is an autosomal recessive trait that affects approximately 7% of the Caucasian population. These individuals (poor metabolizers) carry deficient CYP2D6 gene variants and have an impaired metabolism of severely commonly used drugs. The opposite phenomenon also exists, and certain individuals metabolize the drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine. Restriction fragment length polymorphism analysis of the CYP2D locus in two families with very rapid metabolism of debrisoquine [metabolic ratio (MR) for debrisoquine = 0.01-0.1] revealed the variant CYP2D6 gene CYP2D6L. Eco RI RFLP and Xba I pulsed-field gel electrophoresis analyses showed that this gene had been amplified 12-fold in three members (father and his two children) of one of the families, and two copies were present among members of the other family. The CYP2D6L gene had an open reading frame and carried two mutations causing amino acid substitutions: one in exon 6, yielding an Arg-296-->Cys exchange and one in exon 9 causing Ser-486-->Thr. The MR of subjects carrying one copy of the CYP2D6L gene did not significantly differ from that of those with the wild-type gene, indicating that the structural alterations were not of importance of the catalytic properties of the gene product. Examination of the MR among subjects carrying wild-type CYP2D6, CYP2D6L, or deficient alleles revealed a relationship between the number of active genes and MR. The data show the principle of inherited amplification of an active gene. Furthermore, the finding of a specific haplotype with two or more active CYP2D6 genes allows genotyping for ultrarapid drug metabolizers. This genotyping could be of predictive value for individualized and more efficient drug therapy.

Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6.

Abstract: We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected from a group of 925 individuals previously phenotyped with regard to their capacity to hydroxylate debrisoquine. A significant relationship was found between the scores in as many as 4 of the 15 subscales (psychic anxiety, psychasthenia, inhibition of aggression and socialization) and the debrisoquine hydroxylation capacity. Poor metabolizers were more anxiety-prone and less successfully socialized than extensive metabolizers of debrisoquine. This and a previous study among subjects in Sweden suggest that there may be a relationship between personality and the activity of the enzyme hydroxylating debrisoquine (cytochrome P4502D6). This polymorphic enzyme may have an endogenous neuroactive substrate or product, such as a biogenic neurotransmitter amine.

Why are diazepam metabolism and polymorphic s-mephenytoin hydroxylation associated with each other in white and korean populations but not in chinese populations ?

Abstract: Clinical Pharmacology and Therapeutics (1993) 53, 608–610; doi:10.1038/clpt.1993.77

Frequency of S-mephenytoin hydroxylation deficiency in 373 Spanish subjects compared to other Caucasian populations.

Abstract: We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, healthy Spanish Caucasian subjects, based on the enantiomeric S/R mephenytoin ratio in urine collected 0–8 h and 24–32 h after intake of the racemic drug. Five of the subjects were PM (1.34%, 95% confidence interval 0.18–2.59%), a prevalence lower than in 6 other Caucasian populations, but only significantly lower than in studies in France and Switzerland (P<0.01). We suggest that this difference might be due to the use of different phenotyping procedures.

Disposition of the Neuroleptics Perphenazine, Zuclopenthixol, and Haloperidol Cosegregates with Polymorphic Debrisoquine Hydroxylation

Abstract: Dosage requirements and the therapeutic response vary widely between patients treated with neuroleptic drugs. There are large interindividual differences in the elimination kinetics and in the steady state plasma levels achieved during treatment with a fixed dose of a neuroleptic (Dahl 1986). Thus, pharmacokinetic factors contribute to the variability in drug response. One of the major aims in optimizing neuroleptic treatment has been to search for concentration-effect rather than dose-effect relationships as discussed by Baldessarini et al. (1988). Knowledge of the factors contributing to the pharmacokinetic variability is thus of importance for individualization of drug therapy.

Polymorphism of Debrisoquine and Mephenytoin Hydroxylation among Estonians

Abstract: Debrisoquine and S-mephenytoin hydroxylation polymorphisms were studied in 156 unrelated native Estonians. The hydroxylation phenotypes were assessed by coadministration of mephenytoin with debrisoquine or dextromethorphan. The frequency of the poor metaboliser phenotype of debrisoquine/dextromethorphan was 4.5% (95% confidence interval 1.2-7.8%), and that of mephenytoin was 3.9% (95% confidence interval 0.9-6.9%) among Estonians, which is very similar to what has been reported in other Caucasian populations.

Reproducibility over time of mephenytoin and debrisoquine hydroxylation phenotypes.

Abstract: Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy volunteers with an interval of about one year. The phenotype assignment did not change in any subject for either debrisoquine or mephenytoin. Among extensive metabolisers of mephenytoin, there was a slight increase (P = 0.04) of the mephenytoin-S/R enantiomeric ratio over the study period. The family members of a poor metaboliser of mephenytoin were phenotyped, and the heterozygous extensive metabolisers were found to have higher mephenytoin-S/R ratios than other extensive metabolisers suggesting a correlation between the genotype and the S/R ratio.

Quinidine inhibition of debrisoquine S(+)-4- and 7-hydroxylations in Chinese of different CYP2D6 genotypes.

Abstract: Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba 144 kb allele is almost always a

Molecular basis of drug oxidation polymorphisms

Abstract: The two polymorphisms of oxidative drug metabolism, the debrisoquine and the S-mephenytoin hydroxylation polymorphism, affect the metabolism of a number of drugs including many neuroleptics, antidepressants and certain benzodiazepines. The capacity to hydroxylate debrisoquine is bimodally distributed in Caucasian populations, 5-10% of subjects having a decreased capacity and being classified as poor metabolizers (PM). Deficient debrisoquine hydroxylation is inherited as an autosomal recessive trait and is characterized by the absence of the cytochrome P450 isoenzyme CYP2D6 in the, liver. Several mutated alleles of the CYP2D6 locus causing defect debrisoquine metabolism in PM have been identified. Analysis of leukocyte DNA by polymerase chain reaction (PCR) based amplification with allele specific primers allows the prediction of the phenotype with 92-99% accuracy in Caucasian populations. The presence of two or more copies of an active gene in the CYP2D locus is associated with ultrarapid metabolism of de...