Understand the basis of genetic variability generally and understand the concept of polymorphism in coding and regulatory regions of genes
Genetic variability occurs through two main mechanisms: mutations and crossing over (plus all the other stuff that happens during meiosis). For more information about mutations and their effects, see the following posts. (Kinda regretting not blogging about ANHB1101 now because the stuff in that was probably most relevant to this post. Ah well. On the upside, I didn't waste my time blogging about hominids. *shudders*)
- Nucleic Acids- Mutations
- Mutation and Repair of DNA
- Enzymes Involved in DNA Replication and Repair
- Factors Influencing Development
- Molecular Cell Biology and Disease
Be aware that people can be genetically different in many aspects of drug kinetics (metabolism, especially) and in drug response
When mutations occur, enzymes might fail to function properly (if the mutation is in a gene coding for an enzyme) or someone might lack or have too much of some other important molecule. Enzymes are pretty important in regard to drug metabolism, so someone's levels of a particular enzyme might influence how much drug you need to give them, and so on and so forth.
Be aware that genetic polymorphism is just one part of the overall variability that exists in drug response. Age, diet, smoking, drug interaction and disease are others.
Okay cool, I'm aware now. Moving on...
Understand the example of thiopurine methyl transferase polymorphism
Thiopurine methyl transferase? That's a long name for an enzyme. Good thing it's also known as TPMT.
I'm not going to talk about TPMT straight off the bat though- instead I'm going to tell you a story about another drug called azathioprine.
Azathioprine is a drug used to treat leukaemia and inflammation. The way it does this is by becoming metabolised to form 6-mercaptopurine, which looks a helluva lot like guanine and as such sometimes gets substituted into DNA in place of guanine. This impairs DNA synthesis, which stops leukocytes (white blood cells) from replicating haphazardly. If too much 6-mercaptopurine is produced, however, too many leukocytes might die, leaving the patient open to infection.
Aside from being converted into 6-mercaptopurine, azathioprine can also be converted into two other metabolites. When it is metabolised by xanthine oxidase, an enzyme that everyone has roughly the same level of, it becomes thiouric acid, which is inactive. When azathioprine is metabolised by our old friend TPMT, which is genetically polymorphic (i.e. everyone has differences in TPMT activity), azathioprine becomes methylated and thus inactivated. Both xanthine oxidase and TPMT stop too much azathioprine from being metabolised to form 6-mercaptopurine. Since TPMT levels vary from person to person, it's TPMT that we have to watch out for. Patients with low TPMT activity may find themselves getting sick from too much azathioprine becoming 6-mercaptopurine.
The clinical significance of this is, of course, that screening patients by either measuring blood TPMT or sequencing their genome to see what their TPMT alleles are like (the former being much more practical!) might be important to find a safe and effective starting dose.
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