Hepatic Metabolism Modifier Herbs

Summary

Hepatic Metabolism Modifier Herbs

introduction:
The functional status of hepatic detoxification systems is subject to influence by diverse foods, nutrients and herbal medicines. Many herbs affect the liver, and have traditionally been used by herbalists for centuries to support liver function, aid detoxification and treat hepatic diseases.

Recent research has confirmed traditional uses of these herbs, by examining their mechanisms of action in terms of hepatic detoxification metabolic pathways and in clinical studies. However, only a few of the many hepatic herbs have been studied in depth, the most important being Allium sativum (Garlic), Silybum marianum (Milk Thistle), Glycyrhizza glabra (Licorice Root), Picrorrhiza kurroa (kutkin), Schisandra chinensis (Wu Wei Zi, Chinese Magnolia Vine), Curcuma longa (Turmeric root) and to a degree, Chelidonium majus (Greater Celandine).

overview of pharmacokinetic interactions:

• mechanisms: Specific Cytochrome P450 enzymes (Phase 1) may be subject to either induction or inhibition by hepatoprotective herbs or dietary substances, such as isothiocyanates from the Brassica (Cabbage) family. Phase 2 pathways are commonly affected by increase in glutathione (GSH) levels via actions on glutathione-S-transferase, glutathione peroxidase and glutathione reductase enzyme levels. Other conjugation mechanisms such as glucuronidation may be enhanced by inhibition of beta-glucuronidase, which spares glucuronic acid. Hepatoprotective herbs such as Silybum combine several of these activities. Silybum also increases hepatocyte nucleic acid and protein synthesis and cellular regeneration while displaying anti-oxidant and anti-lipid peroxidation activities. Hypericum extracts are also capable of inducing P450 enzymes, although Hypericum is not generally considered hepatoprotective.

.• research: Research on the Ayurvedic herb Picrorrhiza kurroa suggests that its hepatoprotective activity may be greater than that of Silybum, while the traditional Chinese herbs Schisandra and Bupleurum falcatum also have a range of hepatoprotective activities. Hypericum is also considered by Ernst to be an effective inducer of Cytochrome P450 enzymes.
(Bone K. 1996. 21, 69, 126; Ernst E. Lancet, 354,9195: 1999.)

See also pharmacology entries for:
• Allium sativum (Garlic)
• Glycyrrhiza glabra (Licorice Root)
• Hypericum perforatum (St John's Wort)
• Silybum marianum (Milk Thistle)

overview of interactions:
• herb group affecting drug toxicity: General Hepatoprotection.

• herb group affecting drug class toxicity: Major Anesthetics

• herb group affecting drug class toxicity: Chemotherapy

• herb group affecting drug toxicity: Cisplatin

• herb group affecting drug toxicity: Cyclosporine

• herb group affecting drug toxicity: Haloperidol



Herbs

herb group affecting drug toxicity: General Hepatoprotection.

• general herbal /dietary support: Hepatoprotective herbs and foods may be used to improve liver function before, during and after therapy with pharmaceutical agents likely to cause drug induced hepatoxicity, hepatitis, or otherwise abnormal liver function tests.

• general herbal concern: Hepatoprotective herbs may reduce plasma concentration of essential drugs and alter the dose level required to attain desired therapeutic levels in different compartments. See Cyclosporine below.


herb group affecting drug class toxicity: Major Anesthetics

• research: Preliminary research indicates that silymarin, a combination of the active bioflavonoids in milk thistle, can protect the liver from the type of damage that can result from major anesthetics.
(Fintelmann V. Med Klin 1973;68:809-815.)

• herbal support: Dosage of 140 mg of extracts containing 70-80% silymarin, given three times per day, a week before the surgery and immediately after for at least one week.

herb group affecting drug class toxicity: Chemotherapy

• mechanism: Silymarin is the name of a group of bioflavonoids found in Silybum marianum (Milk thistle). Numerous studies in a variety of settings have demonstrated the ability of these substances to assist the body, especially the liver, in providing protecting against a wide range of toxic substances.

• research: Several studies in laboratory test tubes, in animals and in human subjects have shown the value of silymarin in reducing the toxic side effects of chemotherapeutic agents and in working synergistically with the drugs to enhance therapeutic effects. For example, silymarin compounds have been found to reduce the typical toxic effects of cisplatin upon the kidneys in test tubes and in animals without compromising the drug's anti-tumor activity. Similar tests involving doxorubicin have found similar results.
(Invernizzi R, et al. Haemotologia Haematologica 1993 Sep-Oct;78(5):340-341; Gaedeke J, et al. Nephrol Dial Transplant 1996 Jan;11(1):55-62; Scambia G, et al. Eur J Cancer 1996 May;32A(5):877-882; Bokemeyer C, et al. Br J Cancer 1996 Dec;74(12):2036-2041.)

• herbal support: Individuals undergoing chemotherapy for cancer should consult their treating physician and/or a healthcare professional trained in herbal medicine about potential value of adding Silymarin to their regime before starting such supplementation.

herb group affecting drug toxicity: Cisplatin

• mechanism: Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes and magnesium. Typical symptoms include decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes L-alanine-aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting.

• research: Silymarin is an extract of milk thistle, and silibinin is a key component of this plant extract. In studies using rats Bokemeyer et al concluded that Silibinin protects against cisplatin-induced nephrotoxicity without compromising anti-tumor activity. They found that infusion of silibinin before cisplatin resulted in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Likewise, Gaedeke et al found that the effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Both studies reported that Silibinin given alone had no effect on renal function.
(Bokemeyer C, et al. Br J Cancer 1996 Dec;74(12):2036-2041; Gaedeke J, et al. Nephrol Dial Transplant 1996 Jan;11(1):55-62.)

• herbal support: Individuals receiving cisplatin should consult with their prescribing physician and a healthcare professional trained in herbal medicine before introducing silymarin or derivative herbal products into their treatment regime.

herb group affecting drug toxicity: Cyclosporine

• research: Cyclosporine A (CsA) is metabolized in the liver by cytochrome P-450 3A4. In one study on rats, silibinin, decreased cyclosporine-induced lipid peroxidation but did not exert a protective effect on glomerular filtration rate in the kidneys. Administration of Cyclosporine A in conjunction with Silibinin increased the specific content of cytochrome P-450 in liver microsomes. Another rat study found that silibinin protects the exocrine pancreas from Cyclosporine toxicity. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion.
(Zima T, et al. Ren Fail 1998 May;20(3):471-479; von Schonfeld J, et al. Cell Mol Life Sci 1997 Dec;53(11-12):917-920.)

herb group affecting drug toxicity: Haloperidol

• research: Haloperidol is known to induce liver damage. In a double-blind study involving sixty women taking psychotropic drugs, including haloperidol, Palasciano et al found that 800 mg daily of silymarin, an extract of Silybum marianum, was associated with a significant decrease in free radicals among those taking silymarin as compared to controls.
(Palasciano G, et al. Curr Ther Res 1994;55:537-545.)

• herbal support: Silybum can be used concurrently with Haloperidol therapy to reduce drug hepatoxicity.

Proven hepatoprotective herbs:
• Allium sativum (Garlic)
• Andrographis paniculata (Kirata)
• Bupleurum falcatum (Chai Hu, Hare's Ear Root)
• Chelidonium majus (Greater Celandine)
• Curcuma longa (Turmeric root)
• Glycyrrhiza glabra (Licorice Root)
• Phyllanthus amarus (Bahuputra)
• Picrorrhiza kurroa (Kutkin)
• Rehmannia glutinosa (Di Huang, Chinese Foxglove)
• Schisandra chinensis (Wu Wei Zi, Chinese Magnolia Vine)
• Silybum marianum (Milk Thistle)

Common herbs that may modify hepatic metabolism:
• Aristolochia serpentaria (Virginia Snakeroot)
• Artemisia absinthum (Wormwood)
• Artemisia annuum (Sweet Annie)
• Artemisia tridentata (Sagebrush)
• Baptisia tinctoria (Wild Indigo)
• Berberis vulgaris (Barberry)
• Chelone glabra (Balmony)
• Chionanthus virginicus (Fringetree bark)
• Cynara scolymus (Artichoke)
• Euonymus atropurpureus (Wahoo)
• Eucalyptus spp. (Eucalyptus)
• Gentiana spp. (Gentian)
• Harpagophytum procumbens (Devil's Claw)
• Hydrastis canadensis (Goldenseal)
• Iris versicolor (Blue flag)
• Juglans cinera (Butternut)
• Leptandra virginicum (Black Root)
• Linaria vulgaris (Toadflax)
• Mahonia spp. (Oregon Grape Root)
• Peumus boldo (Boldo)
• Rumex crispus (Yellow Dock)
• Rosmarinus officinalis (Rosemary)
• Taraxacum officinale (Dandelion Root)

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Do not rely solely on the information in this article.

References

Bokemeyer C, Fels LM, Dunn T, Voigt W, Gaedeke J, Schmoll HJ, Stolte H, Lentzen H. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996 Dec;74(12):2036-2041.
Abstract: Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.

Bone K. Clinical Applications of Ayurvedic and Chinese Herbs. Queensland, Australia: Phytotherapy Press, 1996.

Broberg DJ, Bernstein IL. Candy as a scapegoat in the prevention of food aversions in children receiving chemotherapy. Cancer 1987 Nov 1;60(9):2344-2347.
Abstract: The effectiveness of a method for reducing the incidence of chemotherapy-induced learned food aversions was examined. Candy (coconut or rootbeer Lifesavers) was used as a scapegoat and given between the consumption of a meal and the administration of chemotherapy to determine whether this would lead to a greater willingness to consume items in that meal at a future test. This procedure produced evidence that the scapegoat had a significant protective effect: children were twice as likely to eat some portion of their test meal at the time of assessment if they had received the scapegoat at conditioning than when there was no intervention. Thus, the consumption of strongly flavored candies before chemotherapy appears to be a simple and effective way to reduce the impact of chemotherapy on preference for normal menu items.

Ernst E, Second thoughts about safety of St. John's Wort. Lancet, 354, 9195,1999.

Fintelmann V. [Postoperative behavior of serum cholinesterase and other liver enzymes.] Med Klin 1973 Jun 15;68(24):809-815. [Article in German]

Gaedeke J, Fels LM, Bokemeyer C, Mengs U, Stolte H, Lentzen H. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996 Jan;11(1):55-62.
Abstract: BACKGROUND. The anticancer drug cisplatin is know to have toxic side-effects on different segments of the nephron. The flavonoid silibinin has previously been shown to be protective in models of hepatotoxicity. The aim of the present study was to evaluate, whether silibinin can also ameliorate alterations in renal glomerular and tubular function and tubular morphology induced by cisplatin. METHODS. In a rat model renal damage was induced by a single injection of cisplatin (5 mg/kg body weight). The protective effects of silibinin were studied in rats that received the flavonoid (200 mg/kg body weight, i.v.) 1 h prior to the administration of cisplatin. Kidney function was monitored by analysing urinary markers of glomerular and tubular function over a period of 11 days. Animals of a second group, with identical treatment, were sacrificed 4 days after drug application for an evaluation of tubular morphology at the light-microscopical level. RESULTS. Administration of cisplatin caused a decline in kidney function within a day following treatment. Symptoms observed were for example decreases in creatinine clearance and increases in proteinuria, in the urinary activity of the proximal tubular enzymes alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase and in renal magnesium wasting. The effects of cisplatin on creatinine clearance and proteinuria were totally prevented by a pretreatment of the animals with silibinin. Impairment of proximal tubular function was ameliorated, that is enzymuria and magnesium wasting was less pronounced. Silibinin alone had no effect on kidney function. Treatment with silibinin distinctly diminished morphological alterations observed in the S3-segment of the proximal tubule 4 days after cisplatin administration. CONCLUSION. The effects of cisplatin on glomerular and proximal tubular function as well as proximal tubular morphology could totally or partly be ameliorated by silibinin. It is concluded the silibinin can act as a nephroprotectant and it is suggested that it could have beneficial effects on the kidney in clinical settings.

Invernizzi R, Bernuzzi S, Ciani D, Ascari E. Silymarine during maintenance therapy of acute promyelocytic leukemia. Haemotologia Haematologica 1993 Sep-Oct;78(5):340-341. (Letter)

Palasciano G, Portincasa P, Palmier V, Ciani D, Vendemiale G, Altomare E. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res 1994;55:537-545.
Abstract: The efficacy of the antioxidant silymarin in preventing psychotropic drug-induced hepatic damage was evaluated in a double-blind, placebo-controlled study. Sixty patients receiving chronic psychotropic drug therapy were randomly divided into four groups and were treated for 90 days with silymarin or placebo as follows: group IA - treatment with psychotropic drugs and silymarin, 800 mg/d; group IB - treatment with psychotropic drugs and placebo; group IIA - suspension of psychotropic drugs plus treatment with silymarin, 800 mg/d; and group IIB - suspension of psychotropic drugs plus treatment with placebo. Serum levels of malon-dialdehyde (the end product of the oxidation of polyunsaturated fatty acids} and the indices of hepatocellular function were assessed in each patient at baseline (day 0), on days 15, 30, 60, and 90, and 1 month after the completion of treatment. Our data show that silymarin, when used at submaximal doses, reduces the lipoperoxidative hepatic damage that occurs during treatment with butyrophenones or phenothiazines. The study results also suggest that increased lipoperoxidation may contribute to psychotropic drug-induced hepatotoxicity.

Scambia G, De Vincenzo R, Ranelletti FO, Panici PB, Ferrandina G, D'Agostino G, Fattorossi A, Bombardelli E, Mancuso S. Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 1996 May;32A(5):877-882.
Abstract: The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines. Since flavonoids are thought to act through Type II oestrogen binding sites (Type II EBS), silybin binding to Type II EBS was also examined. Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM). Both L and D diastereoisomers of silybin were effective in inhibiting A2780 WT cell growth (IC50 = 14 and 20 microM, respectively). Flow cytometry revealed that silybin decreased the percentage of cells in the S and G2-M phases of the cell cycle with a concomitant increase in cells in the G0-G1 phase. Silybin was able to compete with [3H]E2 for nuclear but not cytosolic Type II EBS. Its affinity parallels its efficacy in inhibiting cell proliferation. Furthermore, silybin (0.1 and 1 microM) potentiates the effect of cisplatin (CDDP) (0.1-1 micrograms/ml) in inhibiting A2780 WT and CDDP-resistant cell growth. Similar results were obtained on MCF-7 DOX-resistant cells when silybin (0.1 microM) was associated with doxorubicin (0.1-10 micrograms/ml). As assessed by the Berembaum isobole method, the effect of silybin-CDDP and silybin-DOX combinations results in a synergistic action. Using the 'stem cell assay' described by Hamburger and Salmon [Science 1977, 197, 461-463], we found that silybin exerted a dose-dependent inhibition of clonogenic efficiency of cells derived from three ovarian tumours (IC50 = 7.4, 4 and 6.4 microM, respectively). Since CDDP and DOX are the two most commonly used drugs for gynaecological tumours, the clinical application of silybin is currently under investigation in our institute.

von Schonfeld J, Weisbrod B, Muller MK. Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity. Cell Mol Life Sci 1997 Dec;53(11-12):917-920.
Abstract: Silymarin can be extracted from the milk thistle, and silibinin is the main component of the plant extract. Possibly due to their antioxidant and membrane-stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. Thus liver, kidney, erythrocytes and platelets have been protected from the toxic effects of ethanol, carbon tetrachloride, cold ischemia and drugs, respectively. The effect of silibinin on endocrine and exocrine pancreas, however, has not been studied. We therefore investigated whether silibinin treatment attenuates cyclosporin A (CiA) toxicity on rat endocrine and exocrine pancreas. Groups of 15 male Wistar rats were treated for 8 days with CiA and/or silibinin. On day 9, endocrine and exocrine pancreatic functions were tested in vitro. At the end of the treatment period, blood glucose levels in vivo were significantly higher in rats treated with CiA while silibinin did not affect glucose levels. In vitro, insulin secretion was inhibited after treatment with silibinin, but amylase secretion was not affected. After treatment with CiA both insulin and amylase secretion were reduced. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion. Despite CiA treatment, amylase secretion was in fact restored to normal with the highest dose of silibinin. Thus silibinin inhibits glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. This combination of effects could be useful in the treatment of non-insulin-dependent diabetes mellitus. Furthermore, silibinin protects the exocrine pancreas from CiA toxicity. As this inhibitory effect is probably unspecific, silibinin may also protect the exocrine pancreas against other insult principles, such as alcohol.

Zima T, Kamenikova L, Janebova M, Buchar E, Crkovska J, Tesar V. The effect of silibinin on experimental cyclosporine nephrotoxicity. Ren Fail 1998 May;20(3):471-479.
Abstract: The immunosuppressive drug cyclosporine A (CsA), is metabolized by cytochrome P-450 IIIA. It causes acute reversible as well as chronic largely irreversible nephrotoxic effects. This effect is bases on vasoconstriction of the afferent and efferent glomerular arterioles which leads to a reduction in glomerular plasma flow and glomerular filtration rate. The mechanisms of the vasoconstriction are unclear with a number of different pathways under discussion. Silibinin is the main constituent of silymarin. Silibinin inhibits lipid peroxidation on hepatic microsomes and mitochondria of rats and is also able to reduce the activity of various monooxygenases. Cyclosporin-induced lipid peroxidation and affected cytochrome P-450 may even contribute to cyclosporine nephrotoxicity. We examined the possibility that silibinin had a protective effect as a result of its radical scavenging properties. Silibinin, 5 mg/kg BW i.p., was administered 30 min before cyclosporine application at dose of 30 mg/kg BW daily i.p. The biochemical parameters, total malondialdehyde (MDA) in whole blood and kidney homogenates and specific content of cytochrome P-450 in microsomal liver suspension were estimated. Three groups were studied: controls (con), cyclosporine alone (CsA), and cyclosporine plus silibinin (CsA + Sili). Creatinine was significantly increased after 2 weeks in both cyclosporine treated groups compared to controls (CsA 60.2 +/- 10.6 versus 45.8 +/- 10.4 mumol/L, p < 0.05; and CsA + Sili 72.0 +/- 8.3 versus 45.8 +/ 10.4 mumol/L, p < 0.001) and glomerular filtration rate (GFR) was significantly decreased (p < 0.0001) in the same groups. Total MDA was elevated only in CsA rats (2.26 +/- 0.35 mumol/L, p < 0.05) in comparison with controls (1.60 +/- 0.44 mumol/L, p < 0.05) and with rats treated by CsA + Sili (1.65 +/- 0.27 mumol/L, p < 0.05). The specific content of cytochrome P-450 in microsomal liver suspension was increased in group CsA + Sili (1.179 +/- 0.115 nmol/mg prot) compared to control group (0.775 +/- 0.086 nmol/mg prot., p < 0.05) and also CsA group (0.806 +/- 0.098 nmol/mg prot., p < 0.05). In conclusion, silibinin decreased cyclosporine-induced lipid peroxidation without a protective effect on GFR. These data indicate that this pathway is not be important in cyclosporine-induced nephrotoxicity. Administration of both drugs (CsA + sili) increased the specific content of cytochrome P-450 in liver microsomes. This suggests that the effect of silibinin on cyclosporine biotransformation in the liver is via cytochrome P-450.