National Toxicology Program

10.0 STRUCTURE-ACTIVITY RELATIONSHIPS

Berberine and protoberberine alkaloids have varying DNA-binding affinities (Smekal et al., 1980; Silikas et al., 1996). Compared to that of berberine, the relative fluorescence intensity of the complexes with DNA decreases in the following order: pseudoberberines, berberines, oxyberberines, tetrahydroberberines, planar derivatives, and protoberberine. Binding properties are influenced by the position and type of substituent, and the presence of charge on the protoberberine skeleton (Smekal et al., 1980). From an analysis of berberine chloride and 12 protoberberine analogues, Silikas et al. (1996) stated that substitution in bulky groups of protoberberine alkaloids inhibited binding to DNA and binding activity of the alkaloids was generally fairly weak. Cushman et al. (1979) found that only the quaternary salts bind with DNA.

In an experiment testing berberine and 12 of its analogues as topoisomerase poisons, it was suggested that increased planarity of berberine may correlate with its enhanced activity as a topoisomerase II poison (Makhey et al., 1995). With cleavage of both methylenedioxy and methoxyl groups from berberine, the compound acts as a potent topoisomerase I poison. Thus, minor variations in the protoberberines may substantially alter their pharmacological properties.

In a study that compared the convulsant potencies of (-)-hydrastine hydrochloride and (+)-hydrastine hydrochloride injected i.v. into male mice, (-)-hydrastine hydrochloride had 180 times less convulsant potency than (+)-hydrastine (Huang and Johnston, 1990).

In male Wistar rat brain synaptic membranes, the concentrations of hydrastine isomers which induced binding to the -aminobutyric acid (GABA) A receptor (measured as the concentrations which displaced 50% of GABA bound to receptor sites, IC50) in a TRIS assay varied: (-)-beta-hydrastine and (±)-beta-hydrastine, IC50 = approx. 1000 M each versus (+)-alpha-hydrastine and (±)-alpha-hydrastine, IC50 = greater than 1000 M each (Kardos et al., 1984).

11.0 ONLINE DATABASES AND SECONDARY REFERENCES

11.1 Online Databases

Chemical Information System Files

CTCP (Clinical Toxicology of Commercial Products)

SANSS

TSCATS (Toxic Substances Control Act Test Submissions)

DIALOG Files

Chemical Econ. Handbook

DIOGENES

Kirk-Othmer Encyclopedia of Chem. Technol.

Federal Register

NIOSHTIC

National Library of Medicine

EMIC AND EMICBACK (Environmental Mutagen Information Center)

STN International Files

AGRICOLA (Agricultural Online Access)

BIOBUSINESS

BIOSIS (Biological Abstracts)

CABA

CANCERLIT

CAPLUS (Chemical Abstracts)

CBNB

CEN (Chemical and Engineering News)

CHEMLIST

CROPB

CROPU

CSNB (Chemical Safety News Base)

DDFB

DDFU

DRUGLAUNCH

EMBASE (Excerpta Medica)

FSTA

HODOC

IPA

LIFESCI

MEDLINE (Index Medicus)

NAPRALERT

PHIN

PROMPT

RTECS (Registry of Toxic Effects of Chemical Substances)

TOXLINE

TOXLIT

TOXLINE includes the following subfiles:

11.2 Secondary References Used

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The Merck Index, 12^th ed., S. Budavari, Ed. Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, 1996. Listed in Section 12 as Budavari (1996).

12.0 REFERENCES

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Anonymous. 1994a. Herbal Harvest Natural Herb: Aloe Vera; Bilberry; Butcher's Broom; Cascara-Sagrada; Cayenne; Dandelion Root; Dong Quai; Echinacea; Eyebright; Feverfew. Product Alert(5 Dec 1994).

Anonymous. 1994b. Liquid Light Children's Herb Supplement: Hear No Evil. Product Alert(20 Jun 1994).

Anonymous. 1994c. Herbal Magic Herbal Formula: Antibiotic. Product Alert(30 May 1994).

Anonymous. 1994d. BioDynamax Guaranteed Potency Herb Supplement: Bilberry; Herb Supplement-Echinacea; Herb Supplement-Ginkgo Biloba; Herb Supplement-Goldenseal. Product Alert(23 May 1994).

Anonymous. 1994e. ProSeed Feminine Rinse. Product Alert(23 May 1994).

Anonymous. 1996a. Chronic diarrhea: Berberine may ease AIDS related diarrhea. AIDS Weekly Plus(7 Oct 1996).

Anonymous. 1996b. Your Life Supplement: Bilberry (Vision) Softgels; Milk Thistle (Mountains Liver Health) Softgels; Dong Quai Softgels; Enchinacea and Goldenseal Softgels; Ginger Softgels. Product Alert(24 Jun 1996).

Anonymous. 1996c. Herbal extracts in a new easy-to-swallow gel cap. Non-Foods Merchandising(Mar 1996):15.

Anonymous. 1997a. Goldenseal. Focus 19(3):4.

Anonymous. 1997b. Goldenseal. Internet Search.

Anonymous. 1997c. Hakuna Matata Children's Liquid Herbal Extract Supplement: Digestive support. Product Alert(26 May 1997).

Anonymous. 1997d. Hakuna Matata Children's Liquid Herbal Extract Supplement: Allergy relief; cold and flu. Product Alert(26 May 1997).

Anonymous. 1997e. Tri-Light Liquid Supplement: Triple Echinacea and Goldenseal. Product Alert(24 Feb 1997).

Anonymous. 1997f. Country Life Liquid Farmacy Supplement: Echinacea supreme; saw palmetto; Children's Echinacea Complex; elder berry; ginkgo biloba; yohimbe; Siberian ginseng; Kava Passiflora Valerian; Echinacea; Goldenseal; Astragalus Schisandra Complex; kava kava root. Product Alert(10 Feb 1997).

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Budavari, S. 1996. The Merck Index. Merck and Co., Inc., Whitehouse Station, NJ. pp. 193-194, 815-816.

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CTCP. 1985. Clinical Toxicology of Commercial Products database.

Cushman, M., F. W. Dekow, and L. B. Jacobsen. 1979. Conformations, DNA Binding Parameters, and Antileukemic Activity of Certain Cytotoxic Protoberberine Alkaloids.

Davidson, M.W., I. Lopp, S. Alexander, and W.D. Wilson. 1977. The Interaction of Plant Alkaloids with DNA. II. Berberinium Chloride. Nucleic Acids Res. 4:2697-2712.

Fang, D.C., G.X. Hu, S.X. Hou, Y. Hu, and M.X. Jiang. 1987. Hemodynamic Effects of Berberine on Conscious Rats. Acta Pharm. Sinica (Yai Hsueh Hsueh Pao)22:321-325.

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FDA. 1989. Regulatory action letter to Manola. DIOGENES record number 187147.

FDA. 1992. Regulatory action letter to Lalut Marketing. DIOGENES record number 190442.

FDA. 1993a. Regulatory action letter to Agape Health Products. DIOGENES record number 191648.

FDA. 1993b. Regulatory action letter to Wishgarden Herbs. DIOGENES record number 190848.

FDA. 1995. Regulatory action letter to Consac Industries. DIOGENES record number 194850.

Federal Register. 1993. Status of Certain Over-the-Counter Drug Category II and III Active Ingredients; Final Rule, May 10, 1993. 12 CFR Part 310.

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Fujita, Y., and M. Tabata. 1987. Secondary Metabolites from Plant Cells-Pharmaceutical Applications and Progress in Commercial Production. Plant Biol. 3 (Plant Tissue Cell Cult.):169-185.

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Kim, D.-I., H. Pederson, and C.-K. Chin. 1991. Stimulation of Berberine Production in Thalictrum rugosum Suspension Cultures in Response to Addition of Cupric sulfate. Biotechnol. Lett. 13(3):213-216.

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Kumar, G.S., D. Debnath, A. Sen, and M. Maiti. 1993. Thermodynamics of the Interaction of Berberine with DNA. Biochem. Pharmacol. 46(9):1666-1667.

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ACKNOWLEDGMENTS

Support to the National Toxicology Program for the preparation of Goldenseal, Berberine, and Hydrastine -Review of Toxicological Literature was provided by Integrated Laboratory Systems, Inc., through NIEHS Contract Number N01-ES-65402. Contributors included: Raymond R. Tice, Ph.D. (Principal Investigator); Bonnie L. Carson, M.S. (Co-Principal Investigator); Robyn H. Binder, M.E.M.; Karen E. Haneke, M.S.; and E. Maria. Donner, Ph.D.

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