Phytochemicals, pharmacogenetics and pharmacokinetics

When one appreciates the extensive range on interactions that exist between phytochemicals essentially entering our bodies through our diet, and the various processes involved in host protection, it becomes very clear that dietary modifications of pharmacokinetic process should be a relative given in our understanding of drug ADME. In fact it should be a central theme in our understanding of interindividual and interpopulational variability in drug behaviour, rather than just being accorded the occasional consideration as a determinant of drug behaviour.

As a corollary, pharmacogenetics cannot hope to fully explain the pharmacokinetic behaviour of any drug in an individual. Environmental chemicals, largely phytochemicals, modify pharmacokinetic processes according to the genetic constitution of the individual, while the genetic makeup of the individual can only be fully expressed in response to environmental chemical effects.

Which leads us to automatically consider what the epigenetic mechanisms might be, in shaping the PK environment of the individual. Perhaps these might be more important than the occasional loss/gain of function variants that we find in the population.

CYP1A2

The CYP1A gene family is a very old one, and the enzyme is found in all vertebrates. In humans there are 2 paralogous members of the family; CYP1A1 expressed predominantly in the lung, and CYP1A2 expressed in the liver.

The CYP1A enzymes very likely evolved to deal primarily with environmental polycyclic hydrocarbons. The activity of CYP1A2 varies considerably and may be easily phenotyped using caffeine as a probe substrate to generate a metabolic ratio.

The metabolic ratio in the population displays a broad unimodality which disguises the fact that the gene is highly polymorphic. The activity of the enzyme is not easily predicted by the genotype as the enzyme is very easily induced by exposure to environmental hydrocarbons. The gene haplotypes may in fact be associated with low or high inducibility of the enzyme.

Inhaled hydrocarbons through cigarette smoking is a common inducer of CYP1A2. In Singapore we are also seasonally exposed to high levels of environmental hydrocarbons as a result of forest fires in the region. The maximum exposure tends to be during dry periods, and when the prevailing winds blow in from the West. These tend to be during the July-November period. It is currently unclear to what extent this has affected our population average CYP1A2 activity.

The most comprehensive examination of CYP1A2 in Chinese is that reported by Chen et al 2005. They were able to demonstrate that haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects. These haplotype pairs account for approximately 6% and 25% of the population respectively.

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.

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.