De K. Sommers

Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients

Abstract. Objectives: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. Methods: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. Results: The genotypes for CYP2D6 predicted a poor metaboliser frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolisers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. Conclusion: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.

Arylamine N-acetyltransferase (NAT2) genotypes in Africans: the identification of a new allele with nucleotide changes 481C>T and 590G>A

This study was carried out to characterize the distribution of NAT2 allelic variants among a sample of three African populations. We determined the frequencies of major NAT2 allele clusters (NAT2*4, *6, *7 and *14) using PCR/restriction fragment length polymorphism and sequencing techniques. The genotypes predict slow acetylator phenotypes of 49, 38 and 52% among Tanzanians, Venda and Zimbabweans, respectively. The most common genotype was NAT2*4/*5. NAT2* 5 was the most common allele while NAT2* 7 was the least common. A new allele with two base changes occurring together, 481C>T and 590G>A, is reported. The frequency of the occurrence of the combination 481C>T and 590G>A, was found to be 9% (30/326), 7% (14/192) and 8% (18/234) among Zimbabweans, Venda and Tanzanians, respectively. The allele has been named NAT2*6E. Among Africans, the change 481C>T is not only associated with 341C>T (i.e. the NAT2* 5 allele cluster) as in other populations, but also with 590G>A on the same allele.

Polymorphism of the 4-Hydroxylation of Debrisoquine in the San Bushmen of Southern Africa:

1 The metabolic oxidation of debrisoquine has been studied in a group of 96 San Bushmen. 2 The amounts of debrisoquine and 4-hydroxy-debrisoquine excreted in 0-8 h urine were measured and the metabolic ratio (% dose as debrisoquine/% dose as 4-hydroxy-debrisoquine) calculated. 3 On the basis of Caucasian criteria, that metabolic ratios > 12.6 represent poor metabolizers, 19% of the Bushmen were poor metabolizers in contrast to the 8-10% found in Caucasian studies. 4 Probit plots showed four modes may be present in the data, which may represent at least three isozymes of the relevant enzyme which may also differ from the Caucasian isozymes.

Non-correlation between Debrisoquine and Metoprolol Polymorphisms in the Venda

1 The metabolic 4-hydroxylation of debrisoquine has been studied in a group of 98 black African villagers in Vendaland. 2 The metabolic α-hydroxylation of metoprolol has been studied in 94 of the same black African villagers. 3 A 4% prevalence of poor oxidative metabolism of debrisoquine and a 7.4% incidence of poor oxidation of metoprolol were found. The 4% result for debrisoquine differs considerably from the 19% found in San Bushmen, 30% in Hong Kong Chinese, 9% in Britains and 0% in Nigerians and Japanese, whilst the 7.4% result for metoprolol compares with 8.4% in Britains but differs from 0% in Nigerians and 4.1% in San Bushmen. 4 None of the poor oxidative metabolizers of debrisoquine were also poor oxidative metabolizers of metoprolol. This is contrary to results in British and Nigerian subjects where defective oxidation of metoprolol co-segrates with that of debrisoquine. 5 No similarities were found between the Venda metabolic ratio (MR) distributions and either extensive or poor MR distributions in Britains or Nigerians.

Metoprolol α-Hydroxylation Polymorphism in the San Bushmen of Southern Africa

1 The metabolic oxidation of metoprolol has been studied in a group of 98 San Bushmen. 2 The amounts of metoprolol and α-hydroxy metoprolol excreted in 0-8 h urine collection, after dosing with 100 mg metoprolol, were measured and the metabolic ratio (% dose excreted as metoprolol/% dose excreted as α-hydroxy metoprolol) calculated. 3 Frequency distribution and probit plots of the metabolic rate data showed a bimodal distribution with 4.1% of the population exhibiting slow metabolism with an MR > 10. 4 These results are much less than found in Caucasians (8.4%) but very different from the unimodal distribution found for Nigerians. 5 A previous study in the same group of Bushmen had revealed that 18 of 96 subjects were poor or non-metabolizers of debrisoquine to 4-hydroxy debrisoquine, but only one of the poor metoprolol metabolizers was a poor metabolizer of debrisoquine. 6 On the basis of these results, the claim of debrisoquine type of polymorphism for β-adrenoceptor antagonists found in Caucasians cannot be extrapolated to the San Bushmen, and one must query the use of debrisoquine as measure of oxidative status in any group other than Caucasians.

Effects of single doses of diazepam, chlorpromazine, imipramine and trihexyphenidyl on visual-evoked potentials.

There is increasing evidence that the P 100 peak of the pattern-reversal visual-evoked potential (VEP-PR) is delayed by drug-induced dopamine antagonism and in Parkinsons disease. Recent studies have reported that components of the flash-VEP (VEP-F) are delayed by an anticholinergic which does not affect the VEP-PR. The present study found that a single dose of chlorpromazine increased the latencies of the VEP-PR and of the VEP-F and increased the VEP-F P2 amplitude. Trihexyphenidyl increased the VEP-PR amplitude but had only minor effects on the VEP-F. There was a tendency for imipramine to increase VEP-F latencies, especially the N3 peak, but had no effect on the VEP-PR. Both VEPs were unaffected by diazepam. These VEP findings add further support to the role of dopamine in the human visual system. Possible reasons are advanced for the failure of trihexyphenidyl to cause previously reported VEP changes associated with hyoscine hydrobromide. Several important issues need to be addressed by future research.

Absence of Polymorphism of Sparteine Oxidation in the South African Venda

1 This study has found no occurrence of poor metabolism of sparteine within a South African Venda populaton of 97 subjects. 2 On the basis of MR (metabolic ratio) the mean and distribution of the results are very similar to those found in Ghanaians.5,14 3 The distribution is also similar to that for fast metabolizers in Caucasians.14 4 It is concluded that different P450 cytochromes are responsible for immediate oxidation of debrisoquine and sparteine, but that both may be activated by the same P450 reductase.

Effects of enhancement and antagonism of 5-hydroxytryptamine activity on the influence of metoclopramide on gastric emptying.

This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying. Six subjects received the following pretreatments before metoclopramide and paracetamol: fluoxetine (5-HT uptake inhibitor); meterogoline (5-HT1 antagonist); pizotifen (5-HT2 antagonist) or methysergide (5-HT1 and 5-HT2 antagonist). One regimen consisted of metoclopramide (5-HT3 antagonist and 5-HT4 agonist) alone. Gastric emptying was measured by the mean cumulative fraction absorbed-time profiles of paracetamol. Methysergide/metoclopramide significantly delayed gastric emptying from 30 min onwards. Metoclopramide with either metergoline or pizotifen did not retard gastric emptying to the same extent, suggesting a greater influence with simultaneous 5-HT1 and 5HT2 blockade. Metoclopramide/fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen. It was assumed that the influence of metoclopramide was not optimal at this stage, therefore possibly indicating domination of 5-HT3 over 5-HT4 effects, resulting in gastric delay. It therefore seems as if all the 5-HT receptors present in the gut have a role to play in the control of gastric emptying.

THE PROPORTIONAL CUMULATIVE AREA UNDER THE CURVE OF PARACETAMOL USED AS AN INDEX OF GASTRIC EMPTYING IN DIABETIC PATIENTS WITH SYMPTOMS OF GASTROPARESIS

1. The foreshortened 2 h method of measuring liquid gastric emptying (i.e. the proportional cumulative area under the curve of paracetamol) was utilized in diabetic patients in order to detect both gastroparesis and the influence of metoclo‐pramide, a known prokinetic drug, on this condition.

Paracetamol Conjugation: An Interethnic and Dietary Study

To test whether dietary or hereditary factors affect paracetamol metabolism, two groups of Venda and a group of Caucasian medical students were investigated. The Venda groups were selected as traditionally living villagers and those who followed a Western life-style. Salivary concentrations of paracetamol and urinary amounts of the glucuronide and sulphate metabolites eliminated over 22 h were determined by HPLC. The metabolite formation rate constants and the percentage of the dose eliminated as each metabolite were calculated. No significant differences were found between the data for total Venda, rural Venda, westernized Venda and Caucasian students for the calculated metabolite parameters. Thus environmental effects showed no apparent influence on the sulphide and glucuronide conjugation of paracetamol, and no hereditary effect was evident between the Venda and Caucasians.