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Research regarding the safety and potential drug interactions of Hydrastis canadensis (goldenseal) and/or its active compounds berberine and hydrastine
This information has been complied in order to facilitate the research efforts of health care professionals and others. These statements have not been evaluated by the Food and Drug Administration and are not intended diagnose, treat, cure, prevent, mitigate, or prevent any disease. The information is presented with the latest publications first. This is an ongoing work so check back often as we will update these pages as more information becomes available. Last Updated : 08/25/2008
A reproductive screening test of goldenseal.
Yao M., Ritche HE, Brown-Woodman PD
Birth Defects Res B Dev Reprod Toxicol. 2005 Sep 28;
BACKGROUND: Goldenseal (Hydrastis canadensis L) is a multi-purpose herb (Hobbs, 1990: Pharm Hist 32:79-82) widely used for its antibiotic properties. It is traditionally contraindicated in pregnancy based on in vivo data but this contraindication has not been confirmed by conventional studies that have been peer reviewed. METHODS: Female rats were dosed by gavage using 65 times the human dose of goldenseal daily on either gestation days (GD) 1-8 or GD 8-15. Controls received an equivalent dose of ethanol. On GD 20, fetuses were weighed and examined for signs of external, internal, or skeletal malformations. Rat fetuses were also explanted on GD 10.5 and cultured with decreasing concentrations of goldenseal for 26 hr. Embryos were examined for growth retardation and malformations. RESULTS: There was no increase in pre- or post-implantation losses. There was no increase in fetal body weight in fetuses exposed to goldenseal. There was no difference in incidence of external or internal malformations. Goldenseal induced toxicity when GD10.5 embryos were cultured for 26 hr in rat serum to which extract was added. CONCLUSIONS: It is likely that poor absorption of goldenseal from the small intestine could explain the discrepancy between the in vivo and in vitro results. It is unlikely that serum concentration from oral treatment could attain the LOEL achieved in vitro. The contrasting results highlight the continuing importance of in vivo work and the necessity of pharmacokinetic data when interpreting in vitro data. The data suggest that goldenseal, at the prescribed human dose, is unlikely to be absorbed to an extent to be unsafe to use in pregnancy despite the apparent cytotoxic effects in vitro. However, these results indicate that pharmacokinetic studies are required to confirm this conclusion. (c) 2005 Wiley-Liss, Inc.
In vivo effects of goldenseal, kava kava, black cohosh,
and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes.
Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB,
Khan IA, Shah A.
Clin
Pharmacol Ther. 2005 May;77(5):415-26.
OBJECTIVES: Phytochemical-mediated modulation of cytochrome P450 (CYP)
activity may underlie many herb-drug interactions. Single-time point
phenotypic metabolic ratios were used to determine whether long-term
supplementation of goldenseal ( Hydrastis canadensis ), black cohosh (
Cimicifuga racemosa ), kava kava ( Piper methysticum ), or valerian (
Valeriana officinalis ) extracts affected CYP1A2, CYP2D6, CYP2E1, or
CYP3A4/5 activity. METHODS: Twelve healthy volunteers (6 women) were
randomly assigned to receive goldenseal, black cohosh, kava kava, or
valerian for 28 days. For each subject, a 30-day washout period was
interposed between each supplementation phase. Probe drug cocktails of
midazolam and caffeine, followed 24 hours later by chlorzoxazone and
debrisoquin (INN, debrisoquine), were administered before (baseline) and at
the end of supplementation. Presupplementation and postsupplementation
phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1,
and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour
sample), paraxanthine/caffeine serum ratios (6-hour sample),
6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and
debrisoquin urinary recovery ratios (8-hour collection), respectively. The
content of purported "active" phytochemicals was determined for each
supplement. RESULTS: Comparisons of presupplementation and
postsupplementation phenotypic ratio means revealed significant inhibition
(approximately 40%) of CYP2D6 (difference, -0.228; 95% confidence interval
[CI], -0.268 to -0.188) and CYP3A4/5 (difference, -1.501; 95% CI, -1.840 to
-1.163) activity for goldenseal. Kava produced significant reductions
(approximately 40%) in CYP2E1 only (difference, -0.192; 95% CI, -0.325 to
-0.060). Black cohosh also exhibited statistically significant inhibition of
CYP2D6 (difference, -0.046; 95% CI, -0.085 to -0.007), but the magnitude of
the effect (approximately 7%) did not appear to be clinically relevant. No
significant changes in phenotypic ratios were observed for valerian.
CONCLUSIONS: Botanical supplements containing goldenseal strongly
inhibited CYP2D6 and CYP3A4/5 activity in vivo, whereas kava inhibited
CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious
adverse interactions may result from the concomitant ingestion of goldenseal
supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and
black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively.
Valerian appears to be less likely to produce CYP-mediated herb-drug
interactions.
Activation of the aryl hydrocarbon receptor by berberine
in HepG2 and H4IIE cells: Biphasic effect on CYP1A1.
Vizl R, Zdarlovia A, Urichlova K, Blaha L, Giesy JP, Dvorak Z
Biochem Pharmacol.
2005 Sep 15;70(6):925-36.
Berberine has long been considered a candidate for an antimalarial drug. It
exerts a plethora of biological activities and has been used in the
treatment of diarrhea and gastro-enteritis for centuries. Here we provide
evidence that berberine activates the aryl hydrocarbon receptor (AhR) in
human hepatoma (HepG2) and rat hepatoma cells stably transfected with a
dioxin responsive element fused to the luciferase gene (H4IIE.luc). AhR was
activated by high doses of berberine (10-50 microM) after 6 and 24 h of
incubation as revealed by CYP1A1 mRNA expression (HepG2) and AhR-dependent
luciferase activity (H4IIE.luc). Berberine induced nuclear translocation of
AhR-GFP chimera transiently transfected to Hepa1c1c7 cells. In contrast, low
doses of berberine (<1 microM) and prolonged times of the treatments (48 h)
failed to produce any activation of AhR in H4IIE.luc cell line. HPLC
analysis ruled out the hypothesis that the loss of berberine capacity to
activate AhR in H4IIE.luc cells is due to metabolic inactivation of the
alkaloid. We demonstrate that berberine is a potent inhibitor (IC50=2.5
microM) of CYP1A1 catalytic activity (EROD) in HepG2 cell culture and in
recombinant CYP1A1 protein. Collectively, our results imply that while
berberine activates the Ah receptor, it is accompanied by inactivation of
the catalytic activity of CYP1A1 and occurs at concentrations that exceed
those predicted to occur in vivo. Given these data, it appears that
activation of the AhR pathway by berberine has a low toxicological
potential.
Final Study Report
Developmental Toxicity Evaluation for Goldenseal Root Powder (Hydrastis
Canadensis) Administered in the Feed to Sprague-Dawley (CDŽ) Rats on
Gestational Days 6 to 20
NTP Study: TER98007
ABSTRACT
Goldenseal (Hydrastis canadensis) root powder is readily available in
over-the-counter (OTC) dietary supplements. Thus, the potential hazards of
oral exposure during pregnancy warranted further investigation. The present
study was designed to evaluate potential developmental toxicity in
timed-mated rats exposed to gold-enseal root powder in the diet throughout
the embryo/fetal period.
In this study, timed-mated Sprague-Dawley (CDŽ) rats were given ad libitum
access to NIH-07 ground feed containing goldenseal root powder (0, 3125,
6250, 12500, or 18400 ppm) from gestational day (gd) 6 to 20. Calculated
intake of goldenseal root powder was 0, 207, 415, 841, and 1215 mg/kg/day
for the control through high-dose groups, respectively. Goldenseal root
powder contained 5% berberine and 4.5% hydrastine by weight. Thus, ingested
doses of these constituents were 0, 10, 21, 42, and 61 mg berberine/kg/day
and 0, 9, 19, 38 and 55 mg hydrastine/kg/day.
Twenty-five timed-mated rats were assigned to each group. Dams were
monitored in-life for clinical signs of toxicity, feed/water consumption,
and body weight. At necropsy (gd 20), the following were evaluated: maternal
clinical condition; body, liver, and gravid uterine weights; pregnancy
status; and number of corpora lutea. In the gravid uterus, numbers of
resorbed, dead, and live fetuses were recorded. Live fetuses were weighed,
sexed, and examined for morphological anomalies [external, (including cleft
palate), visceral and skeletal].
No maternal mortality was observed in this study and there were no
remarkable clinical signs. Maternal body weight was unaffected. Likewise,
there were no significant effects on maternal body weight gain across the
treatment (gd 6 to 20) or gestational (gd 0 to 20) periods. Gravid uterine
weight and maternal corrected body weight gain were likewise unaffected. At
12500 and 18400 ppm, maternal relative feed consumption (g/kg/day) and
maternal body weight gain were transiently reduced during early treatment
(gd 6 to 9). Maternal relative feed consumption was also reduced from gd 9
to 12 at 6250 and 18400 ppm, but there were no significant effects on
maternal body weight or weight gain during the same measurement period.
Effects during early treatment were probably due to altered palatability of
the dosed feed, as suggested by the absence of persistent effects on
maternal relative feed consumption, body weight or weight gain. At 6250 and
12500 ppm, relative maternal water consumption (g/kg/day) was increased from
gd 18 to 20. At ≥6250 ppm, significant dose-related increases were noted for
maternal liver weight (absolute and relative). At the highest exposure
(18400 ppm), average absolute liver weight reached 113% of the average
control weight.
At scheduled necropsy, pregnancy was confirmed in 22-25 (88-100%)
timed-mated females/group. The following endpoints were unaffected: prenatal
mortality (resorptions and/or late fetal deaths), average live litter size,
average fetal body weight per litter (male, female or both sexes) and
percent male fetuses per litter. Likewise, there were no statistically
significant or otherwise distinctive dose-response patterns for
malformations or variations whether pooled by general type (i.e., external,
visceral or skeletal) or considered individually. There were a limited
number of fetuses with multiple malformations, but based on the absence of a
dose-response relationship, these findings did not appear to be
treatment-related.
In summary, CDŽ rats were exposed to goldenseal root powder in feed (0,
3125, 6250, 12500, or 18400 ppm) from gd 6 to 20. Higher concentrations of
goldenseal root powder appear to be unpalatable to the CDŽ rat (NTP 2001h)
and were not included. In this study, the highest concentration yielded an
average daily intake (1215 mg goldenseal root powder/kg/day) that was ~47
times the estimated human intake from dietary supplements (~26 mg/kg/day).
Maternal effects included transient reduction of relative feed consumption
and body weight gain during early treatment, possibly due to altered
palatability, and increased water consumption at the end of gestation.
Maternal liver weights were increased at ≥6250 ppm, suggesting possible
enzyme induction. There was no definitive evidence of developmental toxicity
in this study. Thus, the developmental toxicity NOAEL was ≥18400 ppm, and
the LOAEL was not determined in this study.
Report Date: April 3, 2003
Influence of goldenseal root on the pharmacokinetics of
indinavir.
Sandhu RS, Prescilla RP, Simonelli TM, Edwards DJ.
J Clin Pharmacol. 2003 Nov;43(11):1283-8.
Goldenseal root was identified as the most potent inhibitor of CYP3A4 in a
study that tested 21 popular herbal products for in vitro inhibitory
activity. The purpose of this investigation was to examine the influence of
goldenseal root on the disposition of the CYP3A4 substrate indinavir in
humans. Using a crossover study design, the pharmacokinetics of indinavir
were characterized in 10 healthy volunteers before and after 14 days of
treatment with goldenseal root (1140 mg twice daily). Indinavir was given as
a single 800-mg oral dose, and blood samples were collected for 8 hours
following the dose. No statistically significant differences in peak
concentration (11.6 vs. 11.9 mg/L) or oral clearance (26.8 vs. 23.9 mg*h/L)
were observed following treatment with goldenseal root. Half-life and time
to reach peak concentration were also unchanged by goldenseal. These
results suggest that patients being treated with indinavir can safely take
goldenseal root and that interactions with other drugs metabolized by CYP3A4
in the liver are unlikely.
An in vitro evaluation of human cytochrome P450 3A4
inhibition by selected commercial herbal extracts and tinctures.
Budzinski JW, Foster BC, Vandenhoek S, Arnason JT.
Phytomedicine. 2000 Jul;7(4):273-82.
Serial dilutions of 21 commercial ethanolic herbal extracts and tinctures,
and 13 related pure plant compounds have been analyzed for their in vitro
cytochrome P450 3A4 (CYP3A4) inhibitory capability via a fluorometric
microtitre plate assay. Roughly 75% of the commercial products and 50% of
the pure compounds showed significant inhibition of CYP3A4 metabolite
formation. For each herbal product and pure compound exhibiting
dose-dependency, the inhibition values were used to generate median
inhibitory concentration (IC50) curves using linear regression. Among the
commercial extracts, Hydrastis canadensis (goldenseal), Hypericum
perforatum (St. John's wort), and Uncaria tomentosa (cat's claw) had the
lowest IC50 values at < 1% full strength, followed by Echinacea
angustifolia roots, Trifolium pratense (wild cherry), Matricaria chamomilla
(chamomile), and Glycyrrhiza glabra (licorice), which had IC50 values
ranging from 1%-2% of full strength. Dillapiol, hypericin, and naringenin
had the lowest IC50 values among the pure plant compounds at < 0.5 mM;
dillapiol was the most potent inhibitor at 23.3 times the concentration of
the positive CYP3A4 inhibitor ketoconazole. Utilizing high-throughput
screening methodologies for assessing CYP3A4 inhibition by natural products
has important implications for predicting the likelihood of potential
herbal-drug interactions, as well as determining candidates for further
in-depth analyses.
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