Genetic susceptability

I am an Honours student in the department of Genetics at the University of Adelaide (Australia). A component of our course work involved choosing a topic (related to genetics), researching the background, and giving an experimental approach to prove/disprove a hypothesis. This was a written and oral exercise and the experiments did not have to be carried out.

I am writing to you because I thought you might be interested in what I wrote about. I was initially interested i n why young people are experiencing toxic reactions and dying from ecstasy. We have had a couple of recent "reported" cases (Jan/March 1996) of deaths due to ecstasy in Adelaide. (Which later I found out, from our affiliate member of the department in Forensics, to be due to PMA). I also know that ecstasy use is on the increase in Adelaide because we have a fairly well established rave scene here. (It has built up over the past 3-4 years - as I have grown up really - I am 20). Let me add that I have not tri ed this particular drug.

In humans the cytochrome P450 enzyme CYP2D6 metabolises MDMA into DHMA. There is a well characterised polymorphism of CYP2D6 for many clinically used drugs, and others of similar structure to MDMA such as PMA. Therefore it seems reasonable to say that there will be a CYP2D6 polymorphism for MDMA in the population. This would mean a small percentage of individuals have a defective or absent 2D6 enzyme, and they would not be able to metabolise MDMA into its metabolites (such as DH MA). Therefore there could be a greater concentration of MDMA in the blood for a longer period of time and this could lead to a toxic reaction. The mechanism of action of MDMA is not known in humans so it cannot be predicted where and how the toxic reaction occurs. It is interesting that a lot of deaths are due to hyperthermia (I know these are from hot and crowded conditions at clubs etc.) but this isn't seen with all ecstasy users.

The experiments I proposed were firstly phenotyping a sample human Cau casian population for the extent of MDMA demethylenation. I suggested to do this in California because Dr Grob is using MDMA in human research. Individuals would be given a very low dose (0.25mg/kg) of MDMA and urine and blood levels of MDMA and DHMA (and any other metabolites) would be measured. If there is a difference in MDMA metabolism in the population you would expect a small number of individuals with 100 percent MDMA in their blood/urine. (These individuals would not be able to metabolise MDMA). The se would be classified as 'poor metabolisers' of MDMA and they would be genotyped for the known mutations in the CYP2D6 gene. (i.e. the mutations which define poor metabolisers of ~30 drugs). If the individuals can not be identified as having one of these known mutations, then the CYP2D6 gene would be sequenced and any mutation/s characterised. That is: does the mutation give a defective protein or no protein at all?

That is a brief summary of what I covered in my report; it had to be focused in the mole cular biology area.

From: Julia Kuliwaba jkuliwab@genetics.adelaide.edu.au