Genetic polymorphism of CYP2D6 in a Keralite (South India) population

CYP2D6, which exhibits genetic polymorphism, is involved in the metabolism of more than 40 drugs especially neuroleptics, antidepressants, certain antiarrhythmics and lipophilic β-adrenergic receptor blockers as well as opioids such as codeine [1]. Pronounced interethnic differences in the prevalence of this polymorphism are known to exist. The poor metaboliser (PM) phenotype is present in, for example, 5–10% of European-derived Caucasians [2], less than 1% of Chinese [3] and Japanese [4], 1% of Saudi Arabians [5], 0–2% of black populations [2] 1.2% of Thais [6] and 0–2% of Sinhalese in Sri Lanka [7]. However, the CYP2D6 polymorphism in Indian populations has not been studied extensively. A study among subjects resident in Bombay, which is on the west coast of the central part of India, reported 2% PM with respect to CYP2D6 [8]. A much more recent study shows a frequency of 3% PM in a North Indian population [9]. Since CYP2D6 polymorphism has not been studied in a Keralite population, the present study was undertaken. Kerala is a small state, on the west coast of South India. The nontribal population of Kerala consists of Caucasoid Dravidians, whereas those of Bombay, North India and Sinhalese in Sri Lanka are Caucasoid Aryans [10].

The study was performed in 104 volunteers residing in Kerala, who were mostly students and staff from Mahatma Gandhi University, Kottayam, Kerala. Sixty-four were males and 39 were females in the age range of 17–44 years (mean±s.d. age, 23.5±3.7 years). The mean body mass index±s.d. was 20.7±2.6. All subjects gave their informed consent and the study was approved by the Ethics committee, JIPMER, Pondicherry. All subjects were judged to be in good health as determined by a medical history, physical examination and blood pressure measurement. They were on no medication and drank no alcohol for at least 2 weeks before the study.

After voiding their bladder prior to bedtime, participants ingested 30 mg dextromethorphan (5 ml of Lactuss-LA, cough suspension: FDC Limited, Aurangabad, India). Urine was collected overnight for 8 h. A 20 ml aliquot was stored at −20° C until analysis for dextromethorphan (DM) and dextrorphan (DT) by h.p.l.c [11]. The inter and intraday coefficient of variation for assay of DM and DT (50–8000 ng ml⁻¹) were less than 10% and 5%, respectively. The least quantifiable amount was 20 ng ml⁻¹ for both DM and DT.

The oxidative phenotype assignment was based on the value of the molar urinary ratio of DM to DT (metabolic ratio) in relation to the population antimode. Subjects with a metabolic ratio greater than 0.3 were classified as poor metabolisers with respect to the CYP2D6 enzyme [12].

Ninety-six subjects (92.62%) had metabolic ratios between 0.005 and 0.192 and were classified as extensive metabolisers (EM). Five subjects were identified as PM: four males and one female. They had metabolic ratios between 0.315 and 3.14 (Figure 1). This corresponds to a prevalence of the PM phenotype of 4.8% with a 95% confidence interval of 1.6–10.9%. Three subjects (two males and one female) who had very low metabolic ratios between 0.0034 and 0.0039 may be identified as ultra extensive metabolisers (UEM) with very high enzyme activity [1].

Figure 1.

Distribution of the dextromethorphan metabolic ratio among 104 keralite subjects.

The distribution of the metabolic ratio was not significantly different between male and female subjects (P > 0.05). No side-effects or any adverse drug reactions were observed. The body mass index of the subjects did not significantly influence the metabolic ratio (P > 0.05).

The prevalence of PM in the Keralite population is more than the mean value of approximately 1% observed in other Asian populations [3–7]. The metabolic ratio is determined by factors such as renal drug clearance as well as enzyme activity. Environmental factors may modify these variables which may give rise to differences in the antimode of the metabolic ratio between ethnic groups [6]. However the prevalence of PM with respect to CYP2D6 in the Dravidian population of Kerala differs from that reported in the Indo-Aryan subjects of Sri Lanka, Bombay and North India (0–3%) [7–9].

There is a rightward shift in the frequency distribution curve of dextromethorphan in the Keralite population compared with the Caucasian population studied by Christian et al. (P < 0.001) [13]. However the frequency distribution pattern of the Keralite population is comparable with that reported in a North Indian population (P > 0.05) [9]. A similar interethnic difference in the frequency distribution of the metoprolol metabolic ratio has also been observed between Chinese and Japanese populations [14]. Differences between white subjects and subjects from Kerala in lifestyle, dietary habits, and/or occupation may contribute to this ethnic difference in the activity of CYP2D6.

This is the first study of the pattern of CYP2D6 enzyme activity in the Keralite population. Since this ethnic group has migrated widely to different parts of the world, these results may serve as a basis for further studies to test the relationship between drug oxidation polymorphism and drug induced adverse reactions or diseases of unknown aetiology in Keralites. Further study in other South Indian states can give a clearer picture of the CYP2D6 polymorphism in this region.

We are grateful to Dr Eva Rasmussen, Department of Clinical Pharmacology, University hospital, Uppsala and Dr S. V. Shanbhab, Boehringer Mannheim India Ltd, Maharashtra, India for their generous gift of dextrorphan and dextromethorphan, respectively. We thank all the volunteers who participated in the study.