Posted by Sunnely on July 2, 2001, at 23:08:00
In reply to One person in 20 has a CYP 2D6 gene mutation, posted by Neal on July 2, 2001, at 13:36:09
> "About one out of 20 people has a mutation of the 2D6 gene and therefore lacks the enzyme" says biochemist Ira Herskowitz of the University of California, San Francisco. "Those people are really getting a whopping dose".
The ethnic background of a patient can influence the likelihood that he or she has genetic mutation or "genetic polymorphism." Genetic polymorphism contributes to the classification of an individual as either a "poor metabolizer" (PM) or an "extensive metabolizer" (EM). PMs probably lack a gene for certain cytochrome enzyme and cannot metabolize certain drug substrates well while EMs have the appropriate gene for the cytochrome enzyme and metabolize drugs normally. PMs may achieve toxic blood levels when usual doses of certain drugs are prescribed of them (e.g., CYP2D6-deficient patient can become toxic with normal doses of desipramine or Norpramin), or, if the active drug moiety is a metabolite (daughter compound), they may not achieve the desired pharmacologic effect from the drug (e.g., codeine not being broken down into active compound, morphine therefore, no pain relief; tramadol or Ultram not being broken down into an more active pain-killing compound, M1, therefore ineffective pain relief. Both drugs are called "pro-drugs.").
The incidence of people who are genetically-deficient of the gene for CYP2D6 is about 8% for Caucasians, 4% for African-Americans, 3.4% of Turks, about 1% for Asians, and 16% for Nigerians. The gene for this enzyme is located in chromosome 22.
For the cytochrome enzyme CYP1A2, approximately 6 - 10% of Japanese are genetically deficient of this enzyme. They may become more sensitive to the "normal" amount of coffee. The gene is located in chromosome 15.
For the cytochrome enzyme CYP2C9, approximately 20% of Caucasians and 2% of African-Americans and Asians are genetically deficient of the gene for this enzyme. People who are genetically deficient of this enzyme may achieve toxic levels with normal doses of phenytoin (Dilantin) or naprosyn (Naproxen) and Warfarin (Coumadin).
For cytochrome CYP2C19, approximately 5% of Caucasians, 18% of Japanese, 19% of African-Americans, and 8% of Africans are genetically deficient of this enzyme. People who are genetically deficient of this enzyme may achieve toxic levels with normal doses of some of the antidepressant such as amitriptyline (Elavil), imipramine (Tofranil), clomipramine (Anafranil), moclobemide (Manerix); cyclosphosphamide (Cytoxan, Procytox); diazepam (Valium); the proton pump inhibitors (lansoprazole, omeprazole, pantoprazole, rabeprazole).
CYP2E1 metabolizes many carcinogens and solvents such as ethanol and acetaminophen (Tylenol). The gene is located in chromosome 10. This cytochrome enzyme is responsible for turning Tylenol, when taken in overdose, into potentially hepatotoxic (toxic to the liver) metabolites that can lead to fatality. Also, reason whey Tylenol warning label says avoid combining with alcohol.
It appears that, among the major cytochrome enzymes, CYP3A4 is the only one without genetic polymorphism (i.e., no genetically deficient gene). This is good news because CYP3A4 is responsible for the metabolism of most drugs including psychotropics. It is the most abundant and possibly most clinically important cytochrome enzyme in humans. However, just like the other cytochrome enzymes (except CYP2D6 which is noninducible), it can be inhibited or induced by several drugs leading to toxicity or loss of effectiveness, respectively.
The other route to become a PM (poor metabolizer) of a drug is through drug-drug interaction. When a drug inhibits the metabolism of another drug, the person becomes as if he/she is genetically deficient of a specific cytochrome enzyme involved. For example, Prozac (potent inhibitor of CYP2D6), added to desipramine (Norpramin, heavily dependent on CYP2D6 for metabolism), the person becomes a PM and develops desipramine toxicity (as if he/she were genetically deficient of this enzyme).
Some interesting trivia about cytochrome enzymes:
1. Smokers who are genetically deficient of CYP2D6 are less likely to have lung cancer than smokers who possess a normal CYP2D6 gene. Reason unknown.
2. Patients with double the capacity of CYP2D6 (ultra rapid metabolizers or URMs) are at higher risk for primary liver cancer, possibly due to the activation of mutagens such as nitrosamine.
3. There is an increased incidence of CYCP2D6 mutation in Parkinson's disease patients. They appear to be more sensitive to MPTP (dopaminergic neurotoxin that produced irreversible Parkinsonism). This suggests that CYP2D6 might protect against Parkinson's disease-causing toxins.
For more info on the cytochrome enzyme system and the P450 interactions, check following:
http://www.georgetown.edu/departments/pharmacology/davetab.html
http://www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=704
>
> People with 2D6 mutations can't metabolize codeine, either, which means they can't turn it into its painkilling form, morphine.
poster:Sunnely
thread:68734
URL: http://www.dr-bob.org/babble/20010701/msgs/68772.html