Grapefruits and ....Pomelos

Few people in the west will know about pomelos. Apart from being a really yummy fruit, it is as potent as grapefruit in inhibiting CYP3A4, and MDR1 as well.

Here's my interpretation of the family tree of the pomelo and how it relates to the grapefruit.

Grapefruit, CYP3A4 and deep vein thrombosis

Here's an interesting story off the news:

Grapefruit diet almost cost woman her leg

PARIS, April 3, 2009 (AFP) - A woman who ate a grapefruit each day almost had to have her leg amputated because of a dangerous blood clot, according to an unusual case study reported in the Lancet.

Emergency doctors in Olympia, in the US Pacific coast state of Washington, treated the 42-year-old woman in November 2008 after she was admitted with shortness of breath, dizziness and difficulty walking. An ultrasound scan found she had a large clot blocking the veins of her left leg.

She was in imminent danger of losing the limb to gangrene, but doctors administered a clot-busting drug directly into the blockage and safely dissolved it.

The physicians found she had taken a relatively long car journey, of about an hour and a half, the day before; took a daily dose of oestrogen oral contraceptives; and had a genetic variant, called the factor V Leiden mutation, which is linked to a blood-clot disorder.

All are well-established factors for causing deep vein thrombosis (DVT), as these dangerous events are called.

But what "may well have tipped the balance" is that she had been eating a grapefruit every morning under a weight-loss diet begun three days earlier, the report said.

Grapefruit juice is known to block the action of an enzyme called CYP3A4 which breaks down the contraceptive hormone oestrogen.

This in turn boosts levels of coagulability - the tendency of blood to clot.

Grapefruit juice is broken down only very slowly, which means that it has a cumulative effect if taken daily. Thus, on the third day of her diet, the patient's oestrogen levels would have been many times above normal, helping the clot to form.

DVT has been popularly termed "economy-class syndrome," as it is associated with passengers hunched up on cramped seats in long-haul flights.

But experts say DVT can be inflicted by any kind of immobility - in cars, the office or at home - that causes the leg to be bent for long periods and prevents blood from flowing. The clotting risk is amplified by oral contraceptives and heritability.

Transporters in erythrocytes

Here's something to think about.

The erythrocyte is unique among cells because it lacks a nucleus. At some point in its development, it jetisons the nucleus and and other organelles including mitochondria and lives out the rest of its lifespan circulating as a membrane enclosed sac of haemoglobin and various enzymes.

It is an interesting situation because the erythrocyte, despite having no nucleus survives for an estimated 120 days fulfilling some of most important functions in the body. In the course of its work, as it circulates around the body, it is exposed to a wide variety of endogenous and exogenous chemicals.

The question is 'How does the erythrocyte membrane deal with these chemicals?'. More specifically, what transporters are expressed on the erythrocyte membranes, and what role(s) do they play in health, disease and therapeutics?

Genes vs environment

Not an easy topic, but here is an interesting recent guest column by Sandra Aamodt and Sam Wang, in the New York Times discussing the complex interactions between genes and the environment. Although they discuss this from a largely neuropsychiatric perspective the lessons are widely applicable to therapeutics. We have far too many champions of the genetic approach who push ideas that genetic variability underlie everything that determines drug efficacy and toxicity. The underfunded environmental approaches go largely ignored because they use rather unexciting mundane technology, and produce results that tend not to generate patents.

IMO the gene only approach is clearly not valid. The challenge is how to tease out the various gene-environment interactions and to define them clearly so that they can eventually help us optimize our therapeutic regiments.

Boyanese (Baweanese) in Singapore

Here's an interesting aside following from our previous discussions on ear wax and ethnicities.

A casual discussion with a Boyanese lady revealed that she had wet ear wax. Just an interesting association despite n= 1.

The other interesting nugget of information was that apparently the Boyanese do not classify themselves as Malays on their NRIC (National Registration Identify Card). They are either listed as 'Boyanese' or 'Others'. This is of interest because when we are collecting ethnicity/race information for purposes of medical case studies etc, any 'Malay' data may be under-represented.

The Boyanese originate from a small island off the north coast of East Java. It is of interest to us because many Singaporean Malays trace their heritage back to the original Boyanese settlers. Ethnically they are austronesians like the other Malays. If hospital records use NRIC classifications for ethnicity, and if the Boyanese do not classify themselves on the NRIC as Malays, it may be expected the the Malay data from hospital records will not be very representative.

Aldehyde Dehydrogenase polymorphism

We had previously discussed the alcohol dehydrogenase genetic polymorphism, and had pointed out that among the Han Chinese, there is a high frequency of a genetic variant of alcohol dehydrogenase that allowed a faster conversion of ethanol to acetaldehyde. Acetaldehyde is the chemical that is thought to be responsible for not only the unpleasant effects of alcohol consumption (headaches, flushing etc) but is also thought to be the cause of tissue damage.

There is another enzyme that is responsible for the conversion of aldehyde dehydrogenase to acetic acid. This is called aldehyde dehydrogenase (ALDH). ALDH itself is subject to a genetic polymorphism where the genetic variant ALDH2*2 produces a slower enzyme. Among Han Chinese, the frequency of the ALDH2*2 variant is about 30%.

Among Han Chinese therefore, there is a significant number of individuals who will convert alcohol very quickly to acetaldehyde, and then have a slower removal of acetaldehyde. These individuals build up acetaldehyde concentrations in the blood very rapidly after consumption of alcohol. These individuals are the ones we recognize at drinking parties, who turn red very quickly after low consumption of alcohol.

A recent editorial in Human Genomics 3(2) 2009 highlights the risk this polymorphism poses with respect to the development of esophageal cancers.

So, who are the Thais anyway?

I was thinking about this when I was in Khon Kaen.

It is not an easy question to resolve, as despite the Thais now being numerically so much larger than the Khmers, the Khmers were so much more dominant historically because of the Angkorean civilization. The earliest recognition of a Thai entity only surfaced when the Angkor civilization started to decline.

In early prehistory the region was populated by a Mon language speaking people. Who were they? Most likely people of a Sino-Tibetan stock. On top of this was a distinct amount of 'indianization' as evidenced by civilizations like the Dvararati (pre-angkorean). What 'indianization' really means is not clear, and it is not certain if this was a cultural thing or there was actually an influx of Indian genes as had happened in Cambodia (through the Kambujas from India). In any case, during the Angkor period, the region was 'Khmer-ized', so I am sure there was a substantial of genetic admixture. (See 'So, who are the Khmers anyway?')

As the Khmer civilization ebbed, the Thai people emerged as a distinct entity through the Lavo and Sukhothai kingdoms. A large part of this may have resulted from an influx of Southern Chinese people from Yunnan, fleeing the Mongol invasions.

Thailand now does not recognize differnt ethnicities within the country and everyone is regarded as Thai, although unofficially different ethnic groups are apparent. In a very broad sense, indigenous Thais are generally a sino-tibetan people with a variable amount of Indian admixture. There may be some degree of contribution from the austronesian gene pool, especially in Southern Thailand. On top of these are more recent contributions from Southern China.

So how do we regard pharmacogenetic data from Thailand? I think it becomes important for us to evaluate the source of the data. If it is generated in large urban centres, the contribution of Chinese genes is quite substantial. Indigenous Thai data is best seen in studies conducted in rural communities. In Southern Thailand, one must expect a significant amount of similarity to 'Malay' genetics. In the southern provinces, there still remain pockets of negrito peoples.

This is so far my limited understanding of the situation. I may be wrong. But this is how the current understanding appear to leading us. Perhaps there may be others with a better understanding of Thai ethnicity who can share their experiences and understanding with us?