Dietary Supplements A Framework for Evaluating Safety (2005) / Chapter Skim
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Appendix J: Prototype Focused Monograph: Review of Liver-Related Risks for Chaparral
Appendix J: Prototype Focused Monograph: Review of Liver-Related Risks for Chaparral
Pages 385-449
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From page 385... ...
Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient.
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From page 386... ...
Since about 1969, these same plant components have been used as dietary supplements. Various forms have been available: dried plant material for making teas (water extracts)
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From page 387... ...
. Native populations in the southwestern United States have used chaparral tea for decades without published evidence of toxicity.
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From page 388... ...
Additionally, the product purity and quality were not reported. Clinical trial data: Table B provides a summary of a small clinical trial that was conducted among 59 terminal cancer patients to examine the effect of NDGA and chaparral tea on tumor growth.
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From page 389... ...
ranged from 20 days to "many years." It is notable that Case #15 was the only patient known to use chaparral tea: 4 bags daily for 1.5 years. The product used by this patient was examined using microscopic and chromatographic analysis and was correctly identified as Larrea tridentata with no evidence of biochemical or biological contamination (Sheikh et al., 1997)
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From page 390... ...
B Animal Studies Animal studies on chaparral: There were no animal studies identified that showed liver toxicity as the result of chaparral administration.
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A water extract of the dried leaves was injected into mice intraperitoneally and the LD50 was found to be 10 g/kg body weight for males and 4 g/kg for females (Anesini et al., 1997)
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From page 392... ...
. Likewise, NDGA causes inhibition of the mitochondrial electron transport chain.
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From page 393... ...
. A tea has very little NDGA compared with an alcoholic extract or the powdered dry leaf because NDGA is poorly soluble in water (Obermeyer et al., 1995)
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From page 394... ...
Two informational websites that did not sell chaparral products suggested that people consuming chaparral tea should drink 3 cups a day for a maximum of 2 weeks unless under the care
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. In 1995 AHPA recommended that if member companies chose to sell chaparral, all consumer labeling contain the following informational language: Seek advice from a health care practitioner before use if you have had, or may have had, liver disease.
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. FDA advised chaparral users to stop taking chaparral immediately and to consult a physician if a user had a history of liver disease or was not feeling well (FDA, 1992)
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TABLES ON CHAPARRAL* Table A Chaparral: Individual Components Table B Chaparral: Summary of Adverse Effects in a Clinical Trial Table C-1 Chaparral: Summary of Clinical Case Reports Table C-2 Summary of Clinical Case Reports and a Case Series Report with Chaparral Used in Combination Table D Chaparral: Summary of Adverse Event Reports Table E NDGA: Summary of Animal Studies Table F-1 Chaparral: Summary of In Vitro Studies Table F-2 NDGA: Summary of In Vitro Studies Table G Chaparral: Related Substances that Might Suggest Risk V
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From page 398... ...
Animal studies evaluating NDGA did not exhibit hepatotoxicity, but did exhibit renal proximal tubular damage and cyst formation. In other studies, rodents exhibited both renal and hepatic toxicity in response to the toxic quinone imine from acetaminophen; this involves proximal tubular damage, but not cyst formation.
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From page 399... ...
Traditional uses of chaparral tea by native populations have not revealed reports of hepatotoxicity. Pre-existing liver disease, including excessive alcohol use, hepatitis, or chronic acetaminophen use, may have predisposed some of the individuals to hepatotoxicity.
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From page 400... ...
. Of the 15 reported cases of chaparral-associated hepatotoxicity, only 1 was associated with ingestion of chaparral tea, whereas 11 cases were associated with ingestion of capsules or tablets containing chaparral.
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From page 401... ...
The literature shows that a preponderance of toxicities were associated with preparations other than tea; hepatotoxicity was not reported in a clinical trial of cancer patients drinking chaparral tea. This suggests there that there are differences in the bioavailability of the various components of chaparral that result from differences in the chemical composition of the preparations.
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From page 402... ...
OR [Larrea tridentata] (in any field)
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1981. Additional flavonoids from the leaves of Larrea tridentata.
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1988. Nordihydroguaiaretic acid: Inter- and intrapopulational variation in the Sonoran Desert creosote bush (Larrea tridentata, Zygophyllaceae)
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1988. Ozone impact on the antioxidant nordihydroguaiaretic acid content in the external leaf resin of Larrea tridentata.
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The prophylactic action of the creosote bush (Larrea tridentata) in pigmented cholelithiasis produced by vitamin A
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1989. 1-Aryl tetralin lignans from Larrea tridentata.
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1995. Chemical studies of phytoestrogens and related compounds in dietary supplements: Flax and chap arral.
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1994. Cystic renal cell carcinoma and acquired renal cystic disease associated with consumption of chaparral tea: A case re port.
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-erythrodiol and 3-beta-(4-hydroxycinnamoyl) -erythrodiol from Larrea tridentata.
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From page 411... ...
HO OH animal studies with NDGA Present in all parts of In vitro study: see Table F-2 OH Larrea tridentata, for safety issues from in including leaves, stems vitro studies with NDGA and twigs at 515% of the dry leaf weight (Mabry et al., 1977) Dihydroguaiaretic acid H3CO H3C CH3 In vitro study: weak (Obermeyer et al., 1995)
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From page 412... ...
Lignans, 1-aryl tetralin All of the 1-aryl tetralin lignans are structurally related to podophyllotoxins (Damayanthi and Lown, 1998) H3CO CH3 Isoguaiacin 6 3 No data suggestive of (Konno et al., 1987)
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From page 413... ...
in trace amounts (up to 0.005%) 6-3-Di-O-demethylisoguaiacin No data suggestive of 3-Hydroxynorisoguaiacin, toxicity are available R1=OH, R2=OH (Konno et al., 1987)
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From page 414... ...
tridentata (Sakakibara et al., 1976) Gossypetin 3,7,8,3- No data suggestive of tetramethyl ether toxicity are available Ternatin, R1=CH3, R2=CH3, R3=CH3, R4=CH3 Present in leaves of L
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From page 415... ...
tridentata (Sakakibara et al., 1976) Herbacetin 3,7,8-trimethyl No data suggestive of ether toxicity are available R1=CH3, R2=CH3, R3=CH3, R4=H Present in leaves of L
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From page 416... ...
tridentata (Mabry et al., 1977) Quercetin 3-methyl ether No data suggestive of Isorhamnetin, R1=H, toxicity are available R2=H, R3=CH3, R4=H (Chirikdjian, 1973; Sakakibara et al., 1976)
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From page 417... ...
(Sakakibara et al., 1976) Dihydromyricetin 3,5- H3CO No data suggestive of dimethyl ether 3' 4' OH toxicity are available Dihydrosyringetin 8 HO O (Sakakibara et al., 1976)
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From page 418... ...
tridentata (Xue et al., O HO CH3 1988) O CH3 H3C HO Triterpenes: sapogenins Larreagenin A H3C No data suggestive of Present in the leaves of O toxicity are available L
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, fatty acids (C48C56) (Bohnstedt, 1979; Mabry et al., 1977; Waller and Gisvold, 1945)
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wk Cancer NDGA 4 fever number appeared tumor were attributed or and of there laboratory be tea subjects before American groups: effects: 14 Effects Findings significant could the of evaluated a clinical by In subjects, stimulation abnormalities that chaparral withdrew not Adverse Related Adverse No Total transaminase. Combined published tea, group: subjects: 1×/d mg/d subjects: 1×/d authors tea of oz/d :unknown unknown of the chaparral oral 24 group: NDGA, 3,000 oral of glutamic-oxaloacetic 36 16 23 250 one Number Dose: Route: Frequency: Duration Number Dose: Route: Frequency: Duration: Supplement Chaparral NDGA serum Trial = from wk and white 24 stated total wk SGOT quotes the subjects)
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422 DIETARY SUPPLEMENTS TABLE C-1 Chaparral: Summary of Clinical Case Reports Category/Case/Referencea Number of Subjectsb Date Case #1 1* Sheikh et al., 1997 Case #2 1*
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From page 423... ...
Chaparral capsules, 2,400 mg/d for Subject had fatigue, jaundice, dark urine, 10 d then 800 mg/d for 10 d, taken nausea, abdominal pain, and diarrhea; for allergies and fatigue; estimated recovered within 7 wk cumulative dose of 24.8 g (per Sheikh et al., 1997; actual estimated cumulative dose would be 32 g) 60-year-old female (Sheikh's Diagnosis: chaparral-induced toxic liver patient no.
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424 DIETARY SUPPLEMENTS TABLE C-1 Continued Category/Case/Referencea Number of Subjectsb Date Case #7 1* 3/93 Sheikh et al., 1997 Case #8 1 4/89 Batchelor et al., 1995 Case #9 1 Katz and Saibil, 1990 Case #10 1 Fall/89 Batchelor et al., 1995
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From page 425... ...
Chaparral leaf as tablets Subject presented with a 2-wk history of fluConcomitant medication: none like illness, ascites, and jaundice Patient history: concomitant and Symptoms resolved within 2 mo after long-term alcohol use (14 oz wine/d) cessation of chaparral and alcohol intake; Subject-elected rechallenge: symptoms restarted chaparral without alcohol and recurred upon restarting chaparral within 1 mo symptoms of liver damage without alcohol recurred Subject was readmitted with jaundice, ascites, scleral icterus, and nausea; liver biopsy showed diffuse necrosis with inflammation, portal tract expansion, mild cholestasis, and mild fibrous septation; after 3 mo, symptoms again resolved and a repeat biopsy indicated marked improvement 33-year-old female Diagnosis: drug-induced hepatotoxicity due "Chaparral leaf" (15 tablets/d for to ingestion of chaparral leaf 34 mo, then various amounts)
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Sheikh et al., 1997 Case #15 1* Sheikh et al., 1997 a The numbering of cases is consistent with that used in the full prototype monograph for chaparral, which included a Case #16 and a Case #24.
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13) associated liver damage Chaparral tea, 4 bags of single-ingredient (Sheikh et al., 1997)
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428 DIETARY SUPPLEMENTS TABLE C-2 Summary of Clinical Case Reports and a Case Series Report with Chaparral Used in Combination Category/Case/Referencea Number of Subjectsb Date Liver toxicity Case #17 1* Gordon et al., 1995; Sheikh et al., 1997 Case #18 1 Smith and Desmond, 1993 Case #19 1 Grant et al., 1998
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From page 429... ...
regeneration, acute hepatitis, hepatocyte Concurrent medications: diltiazem HCl, ballooning, portal inflammation, marked atenolol, enteric-coated aspirin, proliferation of bile ducts) nitroglycerin patch, and occasional Subject required a liver transplant and also acetaminophen experienced secondary renal failure Concurrent botanicals: garlic powder, requiring kidney transplant nettle, chickweed tea 36-year-old female Diagnosis: severe acute toxic liver damage Chaparral (2 capsules/d for 8 wk prior following ingestion of chaparral confirmed to onset of symptoms)
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From page 430... ...
430 DIETARY SUPPLEMENTS TABLE C-2 Continued Category/Case/Referencea Number of Subjectsb Date Case #20 1* 7/92 Sheikh et al., 1997 Case #21 1 7/92 Alderman et al., 1994 Case #22 1*
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From page 431... ...
Chaparral tablets, 160 mg/d for previous (See Sheikh et al., 1997) 23 mo, taken to "relieve the craving Subject presented with jaundice without for alcohol" other symptoms; biopsy suggested Patient history: prior alcohol abuse cholangiolitic hepatitis due to drug until 23 mo prior to diagnosis treatment Concurrent prescription drugs: Subject recovered after treatment with clonidine, also lovastatin during prednisone part of the time Concurrent herbals: passionflower, valerium, hops; dandelion extract for a short period 33-year-old female (Sheikh's Diagnosis: chaparral-induced toxic liver patient no.
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432 DIETARY SUPPLEMENTS TABLE C-2 Continued Category/Case/Referencea Number of Subjectsb Date Other toxicity Case #25 1 6/97 Heron and Yarnell, 2001 Case #26 1 5/97 Heron and Yarnell, 2001 Cancere Case #27 1 8/98 Heron and Yarnell, 2001 No toxicity reported Case #28 1 5/97 Heron and Yarnell, 2001
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1) taken at one time Multiherb tincture containing 8% General clinical history and physical chaparral,d 32 mL taken over examination findings were unremarkable; 3.5 mo; proposed as a treatment clinical lab tests were virtually unchanged, for allergies including serum liver enzymes, BUN, Concurrent drug use: estrogens, creatinine, glucose, electrolytes, bilirubin, progesterone, fluticasone nasal spray iron ferritin, lipoproteins, and CBC; no Concurrent herbals use: numerous elevations in liver function tests that would have indicated liver damage (Heron and Yarnell, 2001)
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b Many of the subjects included in Tables C-1 and C-2 as case reports are also included in Table D as Special Nutrition Adverse Event Monitoring System reports and are identified with an asterisk. It was apparent that Case #16 was reported in two publications.
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From page 435... ...
The date of the onset of the malignancy is unknown. In this report the correlation between the subject's cancer and the consumption of chaparral tea seems to have been made on the basis of the known effects of nordihydroguaiaretic acid (the major lignan in chaparral)
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From page 436... ...
1 Chaparral Coma, liver damage NOTE: There were reports in this monitoring system of five additional subjects who took chaparral along with other dietary supplements. These subjects were not considered in this analysis due to the unclear association between the adverse events and the use of chaparral as a result of the concomitant use of multiple dietary supplements.
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ischemia) By histopathologic examination, liver damage was more extensive in the rats treated with NDGA compared with the control (saline-injected)
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From page 438... ...
, 124 wk decreased as compared with controls Early during NDGA exposure, tiny polyps developed along the outer medullary segments of the collecting tubules in the kidney; this likely leads to partial nephron obstruction At 2 mo of NDGA exposure, kidneys were infiltrated by polymorphonuclear leukocytes and macrophages; basement membrane thickening, fibrosis, tubular atrophy, and eventually proximal tubular cell necrosis characterized adjacent to these infiltrate areas By 6 mo of NDGA exposure, cysts were found throughout the kidneys (Evan and Gardner, 1979) Rats (male and female, In 32 out of 33 rats given NDGA, there were cysts of Wistar)
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From page 439... ...
1.0% NDGA (Cranston et al., 1947) NOTE: Acute toxicity studies are defined as a single administration or exposure for less than 24 h; chronic toxicity studies are defined as repeated administration or exposure for 1 mo or longer, combining what some authors call subchronic and chronic (Klassen, 1995)
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From page 440... ...
440 DIETARY SUPPLEMENTS TABLE F-1 Chaparral: Summary of In Vitro Studies Substance Study Design Results and Conclusions Inhibition of enzymes Chaparral, methanol Enzyme assays using rat At 10 µg/mL the chaparral extract (male and female, extract inhibited Sprague-Dawley) liver glutathione S-transferase microsomes incubated At 100 µg/mL the chaparral with 0.1100 µg extract also inhibited chaparral extract/mL aminopyrine N demethylase (various cytochrome P450 forms)
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HT-1080 cells (human epithelial fibrosarcoma cell line) NDGA, 30 µM Cells in culture: NDGA inhibited mediated LN-18 cells (human malignant by CD95 receptor glioma cell line)
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, IC50 0.21 mM cellular respiration and ATP concentration within 1 hr (Pavani et al., 1994) NDGA In cell suspensions: NDGA had cytotoxic NDGA inhibited aerobic and activity (Burk and Woods, anaerobic glycolysis and 1963)
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From page 443... ...
NDGA, LD50 Isolated cells: During a 2-hr incubation 150 µM Rat hepatocytes with NDGA or 21 different flavonoids and polyphenols, NDGA was one of the most cytotoxic, behind galangin and chrysin (Moridani et al., 2002) Inhibition of cellular processes NDGA, Ki Isolated jejunal loops from NDGA inhibited intestinal 140 µM rats (female Wistar)
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NDGA Cells in culture: NDGA inhibited anchorage SW 850 (human pancreatic dependent proliferation cancer cell line) (data not shown)
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NDGA, 100 µM Bovine heart mitochondria NDGA inhibited mitochondrial electron transport (by inhibition of NADH-coenzyme Q reductase and succinate coenzyme Q reductase) (Pardini et al., 1970)
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NDGA Rat liver homogenate NDGA inhibited catechol O (IC50 6 µM) methyl transferase and Human liver homogenate (Burba and Becking, 1969)
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From page 447... ...
NDGA, 10 µM Rat alveolar macrophages and NDGA inhibited Chinese hamster lung fibroblasts phospholipase A2 (Robison et al., 1990) NDGA, IC50 11 µM Human aromatase: NDGA inhibited human Placental microsomes aromatase (estrogen Choriocarcinoma cell line synthetase)
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From page 448... ...
Secoisolariciresinol Cells in culture: Weak cytotoxic activity P-388 (mouse lymphocyte (Shen et al., 1997) leukemia cell line)
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From page 449... ...
Another mechanism by which quinones cause cellular damage is by increasing the oxidative stress of the cell as the quinone/semiquinone pair repeatedly cycle, generating oxygen radicals or other intracellular radicals with each cycle (Jaeschke et al., 2002) NOTE: Only the substances considered to be relevant to the risk of chaparral as a dietary supplement are included in the table.
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