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Biomedical subjects

L Bertilsson

Publications and source records attributed to L Bertilsson.

At least 91 records · Page 5Linked to original sources
PubMed1995

Interphenotype differences in disposition and effect on gastrin levels of omeprazole--suitability of omeprazole as a probe for CYP2C19.

1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Pharmacogenetics in clinical pharmacology and toxicology.

This subject was particularly important to discuss in the presence of Werner Kalow, 77 years young, who is considered as one of the grandfathers of this unique combination of medical research fields. It has become increasingly appreciated that dozens of human drug metabolism polymorphisms exist. The interindividual variabilities in drug metabolism discussed at this symposium do not represent small differences such as 50% or 3-fold but, rather, represent 10- to greater than 1000-fold differences. When attributed to a single gene, dramatic differences can be seen among family members, just as blue and brown eyes can occur in siblings. These differences can result in acute drug toxicity. In addition, there are chronic effects: over one's lifetime, striking differences in the metabolism of drugs, occupationally hazardous chemicals, and other environmental pollutants can lead to interindividual differences in the buildup of DNA damage (e.g., mutations, chromosomal breaks, rearrangements) leading to toxicity and tumor initiation, as well as leading to a buildup in nongenotoxic signals (signal transduction pathways without DNA damage) important for toxicity, tumor promotion, and tumor progression. The human UDP glucuronosyltransferase (UGT superfamily is known to comprise more than 10 genes in humans, and probably in other mammalian species. Breakthroughs in UGT gene mutations responsible for the Crigler-Najjar syndrome and Gilbert's disease have recently been reported. The human cytochrome P450 termed CYP3A4 is a major P450 enzyme in the liver and gastrointestinal tract, and the full impact of the CYP3A4 polymorphism has yet to be fully appreciated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate.

OBJECTIVE: The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate. METHOD: During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method. RESULTS: One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4). CONCLUSIONS: The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies.

Adult↗
PubMed1995

Active hydroxymetabolites of antidepressants. Emphasis on E-10-hydroxy-nortriptyline.

Hydroxymetabolites of the antidepressants nortriptyline and desipramine, like the parent drugs, inhibit neuronal uptake of noradrenaline (norepinephrine). In both plasma and cerebrospinal fluid (CSF), the concentrations of the 10-hydroxymetabolites of nortriptyline (10-OH-NT) are usually higher than those of the parent drugs, but there is a pronounced interindividual variation in the plasma concentrations. This shows that during treatment with nortriptyline, hydroxymetabolites exert, at least in some patients, major effects on brain noradrenaline neurons. Hydroxymetabolites of antidepressants are formed by the polymorphic cytochrome P450 enzyme CYP2D6. Nortriptyline is hydroxylated by this enzyme in a highly stereospecific way to the (-)-enantiomer of E-10-OH-NT. Among Caucasians, 7% are poor metabolisers of the CYP2D6 probe drug debrisoquine. These patients will form very little hydroxymetabolite. The affinity of E-10-OH-NT for muscarinic acetylcholine receptors in vitro was only one-eighteenth of the affinity of nortriptyline for these receptors. In healthy individuals, nortriptyline decreased saliva flow to a significantly greater extent than either E-10-OH-NT or placebo. In an ultrarapid hydroxylator of nortriptyline treated with very high doses of nortriptyline, the plasma concentration of unconjugated 10-OH-NT was very high without any sign of anticholinergic adverse effects. These results show that hydroxymetabolites of nortriptyline have much less anticholinergic effect than the parent drug. When racemic E-10-OH-NT per se was given to healthy individuals, the plasma concentration of the (-)-enantiomer was 5-fold higher than that of (+)-E-10-OH-NT. The 2 enantiomers were eliminated in parallel with an elimination half-life of 8 to 10 hours. A combined in vitro and in vivo investigation showed that a mean of 64% of (+)-E-10-OH-NT was glucuronidated in the liver and subsequently eliminated in urine. Of the administered (-)-enantiomer, a mean of 36% was eliminated as glucuronide formed in the intestine and 35% was actively secreted as unchanged form in urine. Plasma protein binding, determined by ultrafiltration, of the (+)- and (-)-enantiomers of E-10-OH-NT was 54 and 69%, respectively, which is less than that of nortriptyline (92%). The concentration of E-10-OH-NT in CSF was 50% of the concentration of unbound in plasma. There seems to be a stereoselective active transport of E-10-OH-NT from the CSF to blood. We administered racemic E-10-OH-NT to 5 patients during a major depressive episode.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Proteins↗
PubMed1995

Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19.

The isoenzymes which catalyse the polymorphic hydroxylations of debrisoquine/sparteine and S-mephenytoin are cytochromes P450 2D6 and P450 2C19 (CYP2D6 and CYP2C19), respectively. CYP2D6 is involved in the stereospecific metabolism of several important groups of drugs, for example antiarrhythmics, antidepressants and neuroleptics. About 7% of Caucasians but only 1% of Orientals are poor metabolisers (PMs) of debrisoquine. The most common mutated allele CYP2D6B in Caucasian PMs is almost absent from their Oriental counterparts. On the other hand, the mean activity of CYP2D6 in Oriental extensive metabolisers (EMs) is lower than that in Caucasian EMs. This is due to the frequent distribution of a partially deficient CYP2D6 allele causing a Pro34-->Ser amino acid exchange in as many as 50% of Oriental alleles. This is the molecular genetic basis for slower metabolism of antidepressants and neuroleptics observed in Oriental compared with Caucasian people, and consequently for the lower dosages of these drugs used. While CYP2D6 catalyses the metabolism of lipophilic bases only, CYP2C19 is involved in the metabolism of acids (e.g. S-mephenytoin), bases (e.g. imipramine and omeprazole) and neutral drugs (e.g. diazepam). About 3% of Caucasians and 12 to 22% of Orientals are PMs of S-mephenytoin. Polymerase chain reaction-based genotyping techniques recently became available for the two CYP2C19 mutated alleles m1 and m2, which cause no enzyme to be expressed. M1 accounts for about 80% of the mutations responsible for the PM phenotypes in Caucasians, Oriental and Black people. Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians. Omeprazole is to a major extent hydroxylated by CYP2C19, and there is an approximately 10-fold difference in oral clearance between EMs and PMs of S-mephenytoin. The separation of Caucasians from Orientals is fairly recent in the evolutionary process (40,000 to 60,000 years ago); the separation of Black from Caucasian/Oriental people occurred much earlier, about 150,000 years ago. As pronounced differences have been found between Caucasians and Orientals in the CYP2D6 and CYP2C19 enzymes, it might be expected that Black people will show even greater differences in this respect. Some studies have been performed with Black participants, but the picture is not clear. The mean CYP2D6 activity in Black EMs seems to be lower than that in Caucasian EMs and similar to that of Oriental EMs.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents↗
PubMed1995

Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis.

Hydroxylation of debrisoquine, catalyzed by the cytochrome P450 CYP2D6 exhibits genetic polymorphism, with large inter-individual differences in metabolic capacity. About 7% of Caucasians carry deficient CYP2D6 alleles and lack the CYP2D6 enzyme (poor metabolizers). We have shown in two Swedish families, individuals carrying duplicated or amplified functional CYP2D6L-genes (CYP2D6L2), causing the opposite phenomenon, ultrarapid metabolism of debrisoquine. In the present study, the occurrence of extra copies of CYP2D6L-alleles was studied in relation to debrisoquine metabolic ratio (MR) in 270 Swedish Caucasians including 64 selected subjects with very rapid metabolism (MR < or = 0.2). Thirteen of the 64 subjects carried a duplicated CYP2D6-gene as identified by EcoRI and XbaI restriction fragment length polymorphism and allele-specific polymerase chain reaction-amplification of genomic DNA. A new allele with three active CYP2D6L-genes was identified, characterized by an XbaI 54 kilobase fragment. This indicates a preference of the CYP2D6L-gene to be amplified compared to other CYP2D6 genes. Only one subject with an MR higher than 0.2 carried the duplicated CYP2D6L-allele, also being heterozygous for the defect CYP2D6B-allele. The overall frequency of the duplicated/amplified CYP2D6-allele was about 1%, and was present in 40% of subjects with MRs < or = 0.1. Thus, other variant CYP2D6-genes may exist that cause increased CYP2D6 activity. In conclusion, a haplotype with duplicated or amplified functional CYP2D6 genes predicts, with high accuracy, ultrarapid metabolism of debrisoquine. Genotyping for this CYP2D locus variant might be of value in patients not responding to generally recommended doses of CYP2D6 substrates, to distinguish between high metabolic capacity and noncompliance.

Cytochrome P-450 CYP2D6↗
PubMed1994

Quantitation of N-terminally extended tachykinins in cerebrospinal fluid from healthy subjects.

N-terminally extended substance P (SP) and neuropeptide K (NPK), an N-terminally extended form of neurokinin A (NKA), were determined in cerebrospinal fluid (CSF) from healthy human subjects by combined high performance liquid chromatography and radioimmunoassay. The concentrations of the peptides were similar in fresh CSF and in CSF which had been kept frozen for up to 5 months. SP and NKA were not present in measurable amounts in neither fresh CSF nor in CSF that had been frozen. On the other hand, when synthetic SP and NKA were added to approx. 2 pM concentration to fresh CSF samples, both peptides were recovered to 85 and 98%, respectively. There were no significant concentration gradients of the peptides in the first 18 ml (three consecutive 6 ml fractions) of CSF (n = 10). In contrast, we confirmed previous findings, that there are gradients of the amine metabolites 5-HIAA (P < 0.01) and HVA (P < 0.001) (n = 5). The concentrations of extended SP (expressed in SP equivalents) and NPK in the first 6 ml of CSF were 1.5 +/- 0.7 pM and 14.2 +/- 6.4 pM (mean +/- S.D., n = 10), respectively. The present results thus show that the levels of N-terminally extended SP and NKA are stable in frozen CSF samples for up to 5 months. The virtual lack of SP and NKA in CSF does not seem to be due to losses during sample preparation or storage.

Adult↗
PubMed1994

Genetic polymorphism of cytochrome P450. Functional consequences and possible relationship to disease and alcohol toxicity.

The hepatic cytochrome P450 system participates in the oxidative metabolism of numerous endogenous and exogenous compounds. In total several hundred different P450s have been cloned, but it appears that in humans only about 5-10 isoforms account for the major part of drug metabolism. Some of these are polymorphically distributed in the population. Cytochrome P450 2D6 catalyzes the oxidation of over 25 clinically important drugs, eg neuroleptics, antidepressants and lipophilic beta-blockers. Seven % of Caucasians and 1% of Orientals are defective in this enzyme and clearance of drugs metabolized by the enzyme may be substantially decreased in these individuals, with potentially increased risks for side effects caused by the drug treatment. Some individuals are ultrarapid metabolizers and do not achieve therapeutic drug levels at ordinary doses. The molecular genetic basis of these polymorphisms are presented. Methods for genotyping, which can be of predictive value for a more efficient drug therapy, are discussed. Ethanol-inducible cytochrome P450 2E1 (CYP2E1) oxidizes ethanol and acetaldehyde, in addition to over 80 toxicologically important xenobiotics. Furthermore, this isozyme produces reactive oxy radicals which are implicated in the aetiology of alcoholic liver disease. The gene is polymorphic and a mutation in a putative binding site for HNF1, described to affect gene expression, is more rare among subjects with lung cancer as compared to healthy controls. Further studies might give an answer as to whether any of the polymorphic CYP2E1 alleles is associated with the sensitivity to obtain alcoholic liver disease.

Animals↗
PubMed1994

Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism.

The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and of S-mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration-time curves (AUC) for (+/-)-mianserin and (+/-)-desmethylmianserin. Enantioselective high-performance liquid chromatographic analysis of mianserin showed that debrisoquin MR was related to AUC(0-12) for S(+)-mianserin (rs = 0.87; p = 0.001; n = 15) but not for R(-)-mianserin. The ratio between the AUC(0-12) for S(+)-mianserin and that for R(-)-mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserin S/R ratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers of S-mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6-dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)-enantiomer of mianserin.

Administration, Oral↗
PubMed1994

The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline.

Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean C/D of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio C/D in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio C/D was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.

Adolescent↗
PubMed1994

Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service.

Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.

Adult↗
PubMed1994

Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l-1 and the mean AUC(0,24) value was 890 (711) nmol l-1 h. The value of t1/2,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.

Administration, Oral↗
PubMed1994

Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.

Administration, Oral↗
PubMed1994

CSF 5-HIAA predicts suicide risk after attempted suicide.

Suicide risk after attempted suicide, as predicted by cerebrospinal fluid (CSF) monoamine metabolite concentrations, was studied in a sample of 92 psychiatric mood disorder inpatients admitted shortly after attempting suicide. The potential of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF to predict suicide risk within the first year after attempted suicide was studied by means of survival analysis after after median split subgrouping. Eleven patients (12%) committed suicide within 1 year after attempted suicide. Eight of these belonged to the below-the-median (< 87 nM) CSF 5-HIAA subgroup, that is, the suicide risk was 17% as compared with 7% among those with above-the-median CSF 5-HIAA. The cumulative number of survived patient-months during the first year after attempted suicide was significantly lower in the low CSF 5-HIAA subgroup. It was concluded that low CSF 5-HIAA predicts short-range suicide risk after attempted suicide in mood disorder psychiatric inpatients. These findings lend further support to the serotonin hypothesis of suicide risk.

Adult↗
PubMed1994

Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation.

Cytochrome P4502D6 (CYP2D6) catalyzes the oxidative metabolism of several clinically important classes of drugs. Many of these have lower metabolic clearance rates among Chinese, compared with Caucasians, and are prescribed at lower doses for Asian patients. We have now evaluated the molecular genetic basis for this interethnic difference in drug metabolism. The CYP2D loci from two Chinese subjects, one homozygous for the XbaI 44-kilobase haplotype and one homozygous for the XbaI 29-kilobase haplotype, were cloned and characterized. Sequence analysis revealed two variant CYP2D6 genes, CYP2D6Ch1 and CYP2D6Ch2, having mutations yielding two and eight amino acid substitutions, respectively. Exon 9 of the CYP2D6Ch2 gene contained a sequence of 49 bases originating from the pseudogene CYP2D7P. In addition, mutations in the 5' flanking region common to both CYP2D6Ch genes were found. To evaluate the origin of the detrimental mutation in the genes, parts of the 5' flanking regions were introduced into a Hep G2/simian virus 40 expression system with chloramphenicol acetyltransferase as a reporter gene, and transfected cells were analyzed for activity. The ability of the upstream regions to bind nuclear factors was also evaluated using gel-shift analysis. Furthermore, several chimeric constructs of the CYP2D6wt and CYP2D6Ch genes were made, inserted into pCMV2 vectors, and expressed in COS-1 cells. A part of the upstream region of base pairs -1407 to -1068 was found to constitute an enhancer element, but the CYP2D6Ch-specific mutations did not influence the chloramphenicol acetyltransferase activity in the expression system. In contrast, expression of the chimeric genes revealed that the detrimental mutation of the CYP2D6Ch genes was C188-->T, causing a Pro34-->Ser amino acid substitution in a region that is a highly conserved in cytochromes P450 belonging to gene families 1 and 2. This substitution caused expression of a more unstable gene product, as evident from comparison of the relative levels of CYP2D6 mRNA, CYP2D6 protein, and bufuralol 1'-hydroxylase activities in pCMV2-CYP2D6-transfected COS-1 cells. Allele-specific polymerase chain reaction analysis of genomic DNA from 90 Chinese individuals revealed that the CYP2D6Ch1 allele was the most common one and its distribution correlated well with a higher metabolic ratio for debrisoquine. These data demonstrate that important interethnic differences exist in the structure of the CYP2D locus, and they suggest that the frequent distribution of the C188-->T mutation among the CYP2D6Ch genes explains the lower capacity among Chinese to metabolize drugs that are substrates of CYP2D6, such as antidepressants and neuroleptic agents.

Asian People↗
PubMed1993

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

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.

Alleles↗
PubMed1993

N-terminally extended tachykinins in human cerebrospinal fluid.

With HPLC-RIA methods we were unable to demonstrate SP and NKA in measurable amounts in human CSF. Instead N-terminally extended forms of these peptides were found to be present and could be quantitated. The finding that these forms of tachykinins can be released from nervous tissue might suggest that their levels in CSF can be used as markers of the activity in central SP and NKA neurons.

Animals↗