St. John's wort (Hypericum perforatum L.) has been used for centuries to treat a number of common ailments (such as neuralgia, sleep disorders, wound healing, and hemorrhoids), but it is best known for its use in the treatment of mild to moderate depression.(1)  Its use in clinical practice is very common in Germany and other areas throughout Europe and its use in the United States is increasing.(2)  St. John's wort is an herb that is derived from the tops of the flowering parts of Hypericum perforatum L. and is known to have several active ingredients which include cyclopseudohypericin, hypericin, hyperforin, isohypericin, protohypericin, pseudohypericin and several other flavonoids.(2)  The mechanisms of action for the above indications will be released in future newsletter issues. 

Due to the life changing effects of being diagnosed and living with HIV infection, it is not uncommon for this patient population to experience depression, anxiety and related conditions.  Due to a lack of medical care, insurance, social support or other reasons, many patients seek out natural remedies to treat themselves for these conditions.  The problem arises when St. John's wort is taken by HIV patients who are also taking either  protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) based highly active antiretroviral therapy (HAART).(3-6)

Why is this combination a problem?
Unfortunately, St. John's wort is known to reduce the concentrations of both PI's and NNRTI's, thereby resulting in a loss of viral control. In fact, one pharmacokinetic study showed that St. John's wort caused a 57% reduction in the mean area under the curve and an 82% reduction in indinavir (a PI) concentrations.(5)  These reductions are significant enough to induce the development of HIV resistance and/or the loss of viral control. 

What is the mechanism by which St. John's wort does this and why do I need to consider this as a clinician? 
First, it is important to recognize that many antiretrovirals (HIV medications such as PIs and NNRTIs) are known substrates for the cytochrome P450 (CYP450) enzyme system for their metabolism and elimination from the body.(3)  Therefore, anything that affects CYP3A4 in particular, can impact drug concentrations of these antiretrovirals in the body.  Second, St. John's wort is a substrate for the activation of the pregnane X receptor (PXR), which is a well known nuclear receptor found in the cytoplasm of various cells, including liver and gastrointestinal cells.(7)  The PXR is important because it is one of the transcription factors known to influence gene expression of CYP3A4 within the nucleus of hepatic and intestinal cells.(8)  So, any substrate that activates the PXR will increase the gene expression of CYP3A4, thus making more CYP3A4 enzyme available to metabolize more medications.  This ultimately, results in an increased clearance of the known substrates of CYP3A4, such as PIs and NNRTIs medications.    

How does St. John's wort actually do this?
The ingredient, hyperforin, found in St. John's wort is a substrate, or activator, of PXR.  As mentioned before, PXR is a nuclear receptor found in the cytoplasm of cells.  It has 3 major domains that influence its function and level of activity on gene expression.  The first domain, (activation function 1 (AF-1) domain) located at the amino terminus, is where recognition of other transcription factors and/or co-activators cause ligand-independent activation.  The second domain (DNA-binding domain) is the part that directly binds to DNA to modulate gene transcription.  The third domain (ligand-binding domain) on PXR is where substrates, like drugs, bind to "activate" the transcription of more genes.  So, as St John's wort passes through the cell membrane, by diffusion or transport, it will bind to the ligand-binding domain of PXR in the cytoplasm. This causes a dissociation of the histone deacetylase-containing complex (transcriptions co-repressors) so that PXR can then enter the nucleus.  Once in the nucleus of the cell, the ligand-receptor complex either recruits co-activators to form a homodimer or heterodimer with the retinoid X receptor (RXR), where it can now bind to response elements in the promoter and enhancer regions of the target gene.  Once this occurs, gene transcription for CYP3A4 is turned on.  The more CYP3A4 transcribed, the greater the ability to metabolize medications known to be a substrate for CYP3A4, accelerating their clearance from the body.   While not the focus of this newsletter, it is also important to know that the PXR, and this entire process, can each be influenced by genetic polymorphisms causing the full impact of this drug interaction to vary from patient to patient (see future Pharmacogenetics Newsletter issue for more information).  

In conclusion, the concern for this herb-drug interaction was so significant for this patient population that the FDA's Center for Drug Evaluation and Research put out a Public Health Advisory warning patients not to take St. John's wort with their antiretrovirals.(6)  f an HIV patient on HAART requires treatment for depression, it would be prudent to use an antidepressant without enzyme inducing properties.

References:

1. National Center for Complementary and Alternative Medicine: National Institutes of Health.  Herbs at a glance: St. John's wort.  Last accessed on 1-27-2009.
2. Ebadi M.  Pharmacodynamic basis of herbal medicine. 2^nd Ed.  Taylor & Francis Group.  Boca Raton, FL. 2007. 
3. Panel on Antiretroviral Guidelines for Adults and Adolescents.  Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.  Department of Health and Human Services.  November 3, 2008; 1-139. Last accessed 1-27-2009.
4. de Maat MM, Hoetelmans RM, Math t RA et al.  Drug interaction between St John's wort and nevirapine.  AIDS  2001;15:420-1.
5. Piscitelli SC, Burstein AH, Chaitt D et al.  Indinavir concentrations and St John's wort.  Lancet  2000;355:547-8.
6. Food & Drug Administration: Center for Drug Evaluation and Research.  FDA Public Health Advisory - Risk of drug interactions with St John's wort and indinavir and other drugs.  February 10, 2000.  Last accessed on 1-27-2009.
7. Moore LB, Goodwin B, Jones SA et al.  St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.  Proc Natl Acad Sci USA  2000;97:7500-2.
8. Urquhart BL, Tirona RG, Kim RB.  Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs.  J Clin Pharmacol  2007;47:566-78.

St John's Wort, HIV, Hypericum perforatum L, Hypericin, Hyperforin, Pseudohypericin, St. John's Wort, HIV