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The Right Dose

Ethnic differences can have a significant impact on how people respond to drugs.

Ethnic differences in cooking styles, contraception, smoking, and caffeine and alcohol consumption can have a significant impact on how people respond to drugs.

By Vidya Perera & Andrew McLachlan

Diet and lifestyle are rarely considered when assessing how people respond differently to drugs, yet ethnic differences in cooking styles, contraception, smoking, and caffeine and alcohol consumption can have a significant impact – especially in treatments for mental health.

If the same dose of the same drug is given to a group of people, no two responses will be the same – even among identical twins. As Sir William Osler (1849–1919), a famous physician and researcher, stated: “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike”.

Recently we have found that an enzyme involved in the breakdown of medications used to treat mental illness is more active in people of European ancestry compared with people of Indian and Sri Lankan ancestry. As a result, the same drug dose is likely to have a greater impact in people from South Asia.

Ethnicity is often used as an umbrella term to study the wide variability in drug responses. Often, researchers have associated differences in drug response and ethnicity with subtle genetic differences between different populations.

However, it is becoming increasingly recognised that simply capturing the genetic information of different ethnic groups is not enough because ethnicity is complex and multidimensional. Whereas race is a fixed concept that refers to physical features such as skin colour, ethnicity is a dynamic concept that not only encompasses intrinsic factors such as an individual’s genetics and age but also extrinsic factors such as diet and lifestyle. Therefore studying ethnicity provides a means of capturing all the factors involved in drug response variability.

The South Asian population consists of the core countries India, Sri Lanka, Pakistan, Bangladesh and Nepal, and comprises one-quarter of the world’s population. Analysts predict that India will overtake China as the largest population in the world in 2020.

Despite this large population size and high growth rate, relatively few studies have been conducted into drug response variability in this ethnic population. Clearly, studying South Asians could lead to new knowledge about the extrinsic and intrinsic factors involved in drug response.

Enzyme Activity
When a drug is swallowed, it undergoes a number of processes that enable it to carry out its effect on the body and safely pass through an individual’s system. Among these processes, differences in an individual’s ability to metabolise a drug determines the therapeutic outcome. Therefore, variations in the metabolic rate between individuals can be the difference between a drug staying in the body for a longer period of time than is necessary (resulting in toxicity or adverse reactions) or being eliminated from the body too quickly (resulting in a sub-therapeutic effect).

The cytochrome P-450 enzyme family are predominantly responsible for the breakdown of most drugs that enter the body. Of these enzymes, the cytochrome P-450 1A2 (CYP1A2) enzyme metabolises approximately 11% of all therapeutically used drugs.

CYP1A2 has a major role in the metabolism of several antipsychotic medications and also plays a minor role in the metabolism of a number of antidepressant medications. These medications display a high degree of variability in all populations. with patients requiring continual dose adjustments.

One of the reasons it is so difficult to standardise a dose of these medications is that the CYP1A2 enzyme is influenced by a number of commonly consumed dietary and lifestyle factors. Consumption or exposure to these factors can result in an increase or decrease in the levels of this enzyme. This is in contrast to most other drug-metabolising enzymes where an individual’s drug metabolising capacity is predominantly determined by intrinsic factors such as genetics or disease state.

Well-known examples of extrinsic factors that influence this enzyme include cigarette smoke, which results in a 200% increase in activity, and the oral contraceptive pill, which decreases activity by 200–300%. Cigarette smoke contains aromatic and heterocyclic amines that induce CYP1A2 activity, while the oestrogen component of the oral contraceptive pill is believed to inhibit CYP1A2 activity. Of course,the level of induction and inhibition from smoking and oral contraceptive use is directly related to dose, such as how many cigarettes are consumed daily or the dose prescribed for the oral contraceptive pill.

Studies have demonstrated that foods can also impact on CYP1A2 activity. Foods from the crucifer family, such as cauliflower, cabbage, bok choy, broccoli and similar green leaf vegetables, induce CYP1A2 activity. Chargrilled meats are another potent inducer of CYP1A2 activity.

Conversely, foods of the carrot family – including carrots, radishes, grapefruit juice and also tumeric and cumin (spices used in curries) inhibit CYP1A2 activity. Although these foods are known to contain these compounds, relatively few studies have examined how CYP1A2 activity changes following consumption of these foods, and even fewer studies have investigated the interactions between the various inducer and inhibitor foods as well as other extrinsic factors on CYP1A2 activity.

Study Findings
Our study recruited people of South Asian and European ancestry from around the Sydney region. A total of 332 people (166 from each population group) completed a questionnaire about their diet, lifestyle and medication use. CYP1A2 activity of all participants was also measured, and a DNA sample was taken to analyse 13 genes.

We found that CYP1A2 activity in South Asians was significantly lower than in Europeans. Any inter-ethnic difference between two groups is the result of a number of smaller individual factors, and our study aimed to explore what these factors were.

A number of results were similar between the two groups. For example, a significant increase in CYP1A2 activity was found among the smokers in both populations, while a significant decrease in CYP1A2 activity was found among female oral contraceptive users in both populations.

With respect to dietary factors, consumption of 200 mg or more of caffeine daily had a significant increase in both populations, as was heavy coffee consumption.

With respect to dietary foods, consumption of chargrilled meats more than three times per week resulted in a significant increase in CYP1A2 activity in the European population. In contrast, chargrilled meats and other inducer foods had no impact on CYP1A2 activity in the South Asian population.

Interestingly, Europeans who were classified as having a heavy CYP1A2 inducer diet (consuming more than 10 servings of inducer foods in a week) had significantly greater CYP1A2 activity, whereas South Asians on a heavy CYP1A2 inducer diet had a significant decrease in CYP1A2 activity.

While South Asians did consume a wide array of foods that should typically increase the activity of the CYP1A2 enzyme, these foods were often consumed as curries. Curries contain a number of spices and ingredients, including tumeric, cumin, coriander, black pepper and chilli. A number of these affect CYP1A2 activity, but their impact on inducer foods is unknown.

When analysing which of the most important foods, genetic mutations, lifestyle or medication factors were most important in determining CYP1A2 activity, the most important were:

• smoking of cigarettes;
• consumption of medications that are CYP1A2 inhibitors;
• ethnicity (South Asian or European);
• consumption of one or more alcoholic drinks daily;
• gender; and
• daily caffeine intake.

This analysis demonstrates that ethnicity is a significant predictor in determining CYP1A2 activity. However, our analysis was only able to detect 41% of the variation in CYP1A2 activity, indicating that nearly 60% remains unexplained.

Questions Raised
This study opens up a number of questions. At the forefront of this is the question of whether or not South Asians need lower doses of medications metabolised by CYP1A2.

The most relevant area related to CYP1A2-metabolised medications is mental health. A number of antipsychotic medications, including Olanzapine and Clozapine, are metabolised by CYP1A2, and this enzyme also plays a role in the metabolism of several antidepressant medications.

Studies have demonstrated that within the first 5 years of therapy for a psychosis-related issue, up to 80% of patients discontinue treatment due to a lack of improvement of symptoms or inability to deal with the side-effects. Although a number of factors may be responsible for this, the primary issue is the dose of the medicine.

It must be emphasised that being of South Asian or European ethnicity does not recommend a dose. The individual factors that make up each person’s ethnicity, such as caffeine intake and smoking, need to be taken into account, and these are not exclusive to one population. What this study demonstrates is that a population difference exists between European and South Asian CYP1A2 activity.

It is clear that a complex interplay exists between diet, lifestyle and genetic composition. Of course, our findings must be tempered by the fact that more than 50% of the variability remains unexplained, and it is possible that this could be explained by undiscovered genetic differences, although this seems unlikely given relative advances in gene technology.

Clearly, studying ethnic groups provides a way to discover novel environmental, lifestyle and even genetic determinants of drug efficacy. This study demonstrates that combinations of dietary factors also need to taken into account when assessing a drug’s metabolic activity.

Vidya Perera is a doctoral student at the University of Sydney’s Faculty of Pharmacy. Professor Andrew McLachlan is Associate Dean of Research at the University of Sydney’s Faculty of Pharmacy, and Chair of Pharmacy (Aged Care) at Concord Hospital.