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Apologies for length; I lost the original post when my MAC lost charge. If I had more time I'd write a shorter post again. Overall ramifications for ME where CYP is concerned, I don't know. But, at least to me, there's some red flags below we're all familiar w, like NADPH, mito, lipid synthesis, etc.
Along w the doctor, the psychiatrist may not understand the genes/enzymes of interest in your body which act on 1/4th or more presc. meds..... one doesn't need a framed diploma on an office wall to get it lack of knowl. is dangerous, esp. in a multiple script scenario.....
I only know about the following because a shrink gave me serotonin syndrome. Thanks to Dr. Google, & the fact I felt my head was about to explode right off my body, & the fact I had the common sense to immediately cease ingesting citalopram, I figured out I have combined heterozygous genotypes of CYP2D6 and CYP2C19 that are funky. Naturally, the shrink gave me a blank look when I brought this to her attn.
Apparently, it's imp. to know where you fall in these categories with which drugs on what alleles, because four phenotypes exist: poor metabolizers (PM), ultrarapid metablizers (UM), intermediate metabolizers (IM) and normal metabolizers (NM).
"What is cytochrome P450 2D6/2C19?
Cytochrome P450 (CYP) is a family of enzymes that are involved in metabolism – including drug metabolism. Two of the more common enzymes are cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19). DNA variations in the genes that code for these enzymes affect the rate and extent of drug metabolism.
CYP2D6 (cytochrome P450 2D6) acts on one-fourth of all prescription drugs, including the selective serotonin reuptake inhibitors (SSRI), tricylic antidepressants (TCA), betablockers, opiates, neuroleptics, antiarrhythmics and a variety of toxic plant substances. Some 7-14% of the population has a slow acting form of this enzyme and 7% a super-fast acting form. Thirty-five percent are carriers of a non-functional CYP2D6 allele, especially elevating the risk of adverse drug reactions when these individuals are taking multiple drugs. Drugs that CYP2D6 metabolizes include Prozac, Zoloft, Paxil, Effexor, Hydrocodone, Amitriptyline, Claritin, Cyclobenzaprine, Haldol, Metoprolol, Rythmol, Tagamet, Tamoxifen, and the over-the-counter diphenylhydramine drugs, Allegra, Dytuss, and Tusstat. CYP2D6 is responsible for activating the prodrugs codeine and other opioids into their active forms. The analgesic activity of the drugs is therefore reduced or absent in CYP2D6 poor metabolizers. Refer to list for substrates, inhibitors and inducers of CYP2D6.
Therapeutic drug monitoring is recommended in patients with metabolic variations. Keep in mind that subjects with metabolic deficiency will have decreased drug clearance and require additional time to achieve steady-state. In contrast, subjects with increased metabolic activity (UMs) have increased drug clearance and will achieve steady-state sooner that extensive metabolizers. CYP2D6 activity also is dependent upon hepatic and renal function status, as well as age. CYP2D6 activity does not appear to change with age; however, CYP2D6 activity may appear to be altered because of age-associated changes in hepatic blood flow or a decrease in renal elimination of metabolites.
Tricyclic antidepressants, such as imipramine and amitriptyline, and phenothiazine antipsychotics, such as thioridazine, inhibit cardiac potassium channels. Individual risk for drug-induced prolongation of the QT interval was shown to be related to genetic variants in genes encoding cardiac K+-channels, such as the HERG gene encoding for a K+ channel subunit.
If CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, than poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into CYP2D6 and CYP2C19 genotype-based dose recommendations for ...a substance that has a greater effect than its parent chemical, then extensive metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.
Why would I test for variations in CYP2D6 and CYP2C19 when monitoring prescription drugs?
Genetic variations in a patient’s CYP2D6 and CYP2C19 genes can help explain unusual results observed:
* Some prescription medications are converted/metabolized to a more active form. If the patient is a poor metabolizer, he/she may not experience adequate pain relief.
Most CYP is anchored to membranes of the microsomal portion of the cell. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum.
Knowledge of the P-450 system is critical in understanding drug metabolism and drug interactions. Listed below are 3 links that will show 3 different tables: The first table shows what cytochrome system is involved in the metabolism of various drugs (substrates). The second table shows various drugs and the various cytochrome P-450 enzyme systems that either inhibit or induce that drugs metabolism. Lastly the third table shows the various cytochrome P-450 enzyme systems and shows what drugs induce or inhibit the various enzyme systems.
Table 1 - Various Drugs and the P-450 Systems Responsible for Their Metabolism
Table 2 - Various Drugs and the Variuos P-450 Enzymes that Inhibit or Induce their Metabolism
Table 3 - Various P-450 systems and What Drugs Inhibit or Induce the Enzyme System
Table 4 - Drugs / Foods that Induce or Inhibit Various Cytochrome P-450 Systems and the Drugs that are effected by this Induction or Inhibition.
Tricyclic antidepressants, such as imipramine and amitriptyline, and phenothiazine antipsychotics, such as thioridazine, inhibit cardiac potassium channels.307 Individual risk for drug-induced prolongation of the QT interval was shown to be related to genetic variants in genes encoding cardiac K+-channels, such as the HERG gene encoding for a K+ channel subunit. If the patient is a nursing mother and an ultra-extensive metabolizer, codeine therapy should be carefully controlled to prevent neonatal morphine toxicity.
Codeine is ineffective at typical doses in up to 10% of Caucasians carrying two nonfunctional CYP2D6 alleles.
Asians, Pacific Inlanders, African and African Americans have higher percentages of reduced functional or non-functional CYP2D6 alleles (between 40% and 50%) than do Europeans (26%). Therefore the percentages of PMs in the former groups are most likely higher. Pacific Islanders have a high frequency (41%) of a reduced functional allele CYP2D6*10, indicating slower metabolism. Non-functional PMs and reduced function IMs represent about 50% of African populations (non functional CYP2D6*17 represents 35% of allele variation). African Americans show twice the allele frequency of PMs compared with Africans (14.5% vs 6.3%). CYP2D6 activity also is dependent upon hepatic and renal function status, as well as age.
What is polymorphism?
In different people and different populations, activity of CYP oxidases differs. Genetic variation in a population is termed 'polymorphism' when both gene variants exist with a frequency of at least one percent. Such differences in activity may have profound clinical consequences, especially when multiple drugs are given to a patient. There are profound racial differences in the distribution of various alleles - data on a drug that works in one way in one population group cannot necessarily be extrapolated to another group.
Is enzyme induction of CYP important?
Yes. Although most of the CYPs can be induced (the notable exception being 2D6), perhaps the most important in this regard is CYP3A4. 3A4 is the most prevalent CYP in the body, and metabolises many substrates. The most important inducers of 3A4 are antimicrobials such as rifampicin, and anticonvulsants like carbamazepine and phenytoin, but potent steroids such as dexamethasone may also induce 3A4. The long list of agents metabolised by the enzyme include opioids, benzodiazepines and local anaesthetics, as well as erythromycin, cyclosporine, haloperidol, calcium channel blockers, cisapride and pimozide. Oral contraceptives are also metabolised, and their efficacy may be impaired when an inducer such as rifampicin is taken.
Function
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, omeprazole, diazepam and some barbiturates.
Even more important than the inducers of 3A4 are the inhibitors. There is a long list - azole antifungals, HIV protease inhibitors, calcium channel blockers, some macrolides like troleandromycin and erythromycin, and the commonly used 'SSRI' antidepressants. Lethal clinical consequences can result from combining 3A4 inhibitors with drugs that are metabolised by this cytochrome. Non-sedating antihistamines have resulted in fatal arrhythmias, as has occurred with cisapride administration in combination with an inhibitor. Erythromycin in combination with theophylline may cause toxicity due to the latter.
The clinical consequences of CYP polymorphism, inhibition and inducibility have already been mentioned. Unfortunately, these are potentially so complex that whenever you give a drug you should ask whether it has an effect on a CYP isoform, and whether it is metabolised by CYP.
David Flockhart has composed (and maintains) a superb table of interactions at Georgetown University. Visit it! You may also wish to wander by Ed Hayes' excellent CYP page.
Also: http://snpedia.com/index.php/CYP2D6
Is CYP important in cancer?
There has been much speculation about the role of the various CYP proteins and polymorphisms as causes of cancer. Some CYPs may activate pro-carcinogens to carcinogens; many are probably involved in the removal of carcinogens from the body. In addition, several cancers are hormone sensitive, and those CYPs involved in, for example, steroid or retinoic acid metabolism may play a crucial role in suppression or promotion of malignancies through such metabolism.
For specific dosages see charts and tables adapted from Julia Kirchheiner, et al Molecular Psychiatry Feature Review, 9 442-473 (2004), "Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response," a meta analysis of published research from 1970-2003 on the relevance of pharmacogenetic effects of CYP 2D6 and CYP 2C19 on 36 antidepressants and 38 antipsychotics.
Cytochrome P450 chemistry is fascinating and challenging. Note that the bond between the two atoms in an oxygen molecule is rather strong. This implies that a substantial amount of energy is required to break the bond - energy that is supplied by addition of electrons to the iron atom of heme. These electrons in turn come from the last protein in an "electron transfer chain". There are two such chains in cells that end up at P450. The first is in the endoplasmic reticulum (ER), and the protein involved is called NADPH cytochrome P450 reductase - electrons pass from NADPH to FAD to FMN and thence to heme. The second chain lurks within mitochondria. A complex bucket brigade of proteins hands the electrons down to heme. NADPH passes electrons to ferredoxin reductase, thence to ferredoxin (which itself has an iron-sulphur cluster), and from there to CYP. }
o Cytochrome P450 Drug Table
"To the Editor: There have been a number of reports that combination therapy with tramadol and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine +(1), paroxetine +(2), and sertraline +(3) can lead to serotonin syndrome. Citalopram monotherapy has also been described as leading to serotonin syndrome +(4), but we believe this has not yet been observed under coadministration with tramadol."
(Yeah? TRY ME. I got chur "anecdotal" right here. The above is eerily akin to physician attitude toward ME.... "Anecdotal" needs dictionary revision to include "Hasn't experienced it him/herself".) I figured out I'm a heterozygous carrier of deficient alleles for both enzymes, bc metabolizing capacity of both pathways was reduced, hence the weirdest sensation I've ever had in my head..... Last, a friend was on NINETEEN diff. prescriptions & morphing into Jack Nicholson in The Shining.... Asked if his docs knew his CYP genotyping.... he asked & they didn't even know what he was referring to.
And.... careful with herbs like St. Johns Wort.. teas, etc.... I take a lot of herbs & triple-check interactions now.
Have you tried Minipress for sleep? Works like a charm for me and I only take 1mg.
I haven't seen any evidence for what DeMeirleir suggests, neither from science nor from ME patient experience. There is, however, quite a bit of evidence for an alternative explanation, namely that the day-and-night cycle in ME is disturbed. That is a hormone problem, not an immune system problem.
Indeed. Many of us know just how difficult it is to arbitrarily change one's circadian rhythms.