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
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
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
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
- 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.
- Ebadi M. Pharmacodynamic basis of herbal medicine. 2nd Ed. Taylor & Francis Group. Boca Raton, FL. 2007.
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.
- de Maat MM, Hoetelmans RM, Math t RA et al. Drug interaction between St John's wort and nevirapine. AIDS 2001;15:420-1.
- Piscitelli SC, Burstein AH, Chaitt D et al. Indinavir concentrations and St John's wort. Lancet 2000;355:547-8.
& 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
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.
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