Cytochrome P450, Drug Interactions, & Secondary Porphyria
I’ve read a good deal of discussion about these issues since starting on CAP. Perhaps I’ve overlooked something in the archives, but I’ve read some recent sources that have given me new information about this complex topic.
Cytochrome P450 (CYP) is an isoenzyme, so called because it is closely related to other variants by homologous genes. They are named by a root (CYP), family (a number), a subfamily (a letter), and then the gene (another number). So, for example, one isoenzyme goes by the name of CYP2D6. CYP isoenzymes in the same family and subfamilies share structural similarities. The name comes from the fact that the cellular proteins in these enzymes have pigments that absorb light at wavelengths near 450 nm. These enzymes metabolize drugs, toxins and other substances, so they can be safely eliminated from the body. They are critical to the first phase of metabolism that makes a substance (or substrate) water soluble through an oxidation process. If the substrate is not transformed into a form that can be rapidly eliminated, then a second metabolic phase is undertaken (conjugation reaction) that adds a small endogenous molecule to make the substrate water soluble. As previously discussed here, most of the CYP metabolization occurs in the liver. Here’s a site listing all the different genetic expressions of CYP, but 90% of the processing is done by six: 1A2, 2C9, 2C19, 2D6, 2E1, 3A4,5,7. 50% of all drugs are metabolized by CYP3A4,5,7.
Each CYP isoenzyme has a list of substrates that it can process. Some substrates can be processed by more than one enzyme. Each enzyme also has a list of substrates that can inhibit or induce metabolization. If metabolization is inhibited, all substrates that are processed by that enzyme stick around longer and at higher concentrations and therefore are more potent. When metabolization is induced, then all the substrates processed by that enzyme are eliminated more rapidly and so they are less potent. Many of the new drugs that are more potent (or have a longer half-life) achieve that effect by inhibiting the enzyme that processes them.
You have to watch out for interactions between substrates. For example, if you take Lovastatin for high cholesterol, you are advised not to eat grapefruit or drink grapefruit juice. This is because Lovastatin is processed by CYP3A4,5,7 but grapefruit juice is a moderately strong inhibitor of this enzyme. The interaction would increase the potency of Lovastatin and any other any other drug you take that is processed by CYP3A4,5,7.
Several other factors can affect CYP isoenzyme activity. Genetic and age differences are modulators for some enzymes. 5-10% of Caucasians are slow metabolizers for the 2D6 enzyme, and 20% of Asians are slow for the 2C19 enzyme. The activity of the isoenzyme 3A4,5,7 declines with age, so drugs that are processed by this enzyme become more potent as you get older. However, 2D6 does not change with age. Bacterial endotoxins (lipopolysaccharides - LPS) and inflammation from cytokines also decrease CYP enzyme activity.
CYP enzymes contain a heme iron center which is why they can induce secondary porphyria. When CYP substrates are ingested, the liver produces more heme precursors to process them. Too much demand can lead to secondary porphyria, particularly as suggest by Dr. Stratton, when the liver is infected with C. pneumoniae.
Here is a list of some of the medications and supplements prescribed by both the Stratton and Wheldon protocols and their effects on the some of the main CYP enzymes, as described by Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed June 5, 2008.
Substance Substrate Inhibit Induce
Cimetidine 1A2 (Weak)
2C19, 2D6 (Weak),
Clarithromycin 3A4,5,7 3A4,5,7 (Strong)
Duloxetine 2D6 2D6 (Mod)
Isoniazid (INH) 2C9, 2C19, 2E1
Omeprazole 2C19 2C19 (strong) 1A2
Rifampin 2B6, 2C8,
Table 1. CAP drugs, their CYP enzyme substrate, and modulatory CYP effects.
So, what can you conclude from this information? First, pay attention to interactions among drugs and supplements that are metabolized by CYP enzymes. Early in my treatment for CFS, my doctor prescribed both Cymbalta (duloxetine) and Wellbutrin (bupropion). Although not listed in this table, you can find from Dr. Flockhart’s tables that bupropion is a strong inhibitor of the 2D6 enzyme used to metabolize duloxetine. Combine this interaction with the possibility that I am one the 10% of Caucasians who are slow 2D6 metabolizers, and you have a plausible explanation why after a few months duloxetine became toxic for me to take. Recently on the cpnhelp.org site, there was some discussion about rifampin. It induces metabolization in most of the major CYP enzymes, so the potency of other concomitant drugs or supplements processed by CYP might be weakened. Jim reported on a article that showed Vitamin D depletion by rifampin. Vitamin D is degraded by CYP24A1, so apparently rifampin can speed up metabolization in many different forms of CYP. Probably a good idea, as Daisy suggested, to take rifampin at a different time from your other medications and supplements.
Second, to reduce secondary porphyria cut down on substances that require CYP metabolization. Here’s a list of drugs that can create problems. You also can look at Flockhart’s table for other CYP substrates.
Finally, note that not all the antibiotics we use are metabolized by CYP. About a month ago, I started on the revised Stratton protocol, changing from azithromycin to clarithromycin. I’ve had a much harder time with porphyria symptoms since making the change. Clarithromycin is processed by the CYP 3A4,5,7 enzyme and also is a strong inhibitor of it as well, which is why the antibiotic is potent. Azithromycin is metabolized by biliary elimination and not CYP. This change in medication has increased the demand for CYP in my system, and perhaps produced more heme precursors that cause porphyria.
CFS since 1/07. Pall anti-oxidant protocol since 8/07 with IM hydroxo-B12. Dx 3/08: Cpn, EBV, CMV. Valtrex since 3/08. CAP since 4/08: Biaxin 500 mg BID, NAC 1200 mg BID, Flagyl 500 mg BID pulse every 3 weeks.