Nordihydroguaiaretic acid: Hepatotoxicity and detoxification in the mouse

Joshua D. Lambert, Dedun Zhao, Ross O. Meyers, Robert K. Kuester, Barbara N. Timmermann, Robert T Dorr

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Larrea tridentata (Moc & Sess) Cov. (Zygophyllaceae) is an ethnobotanically important plant found in the American Southwest and northern Mexico. Although numerous beneficial effects have been attributed to this plant, several case reports have demonstrated high doses of Larrea-containing herbals induce hepatotoxicity and nephrotoxicity in humans. Nordihydriguaiaretic acid (NDGA) is a lignan found in high amounts (up to 10% by dry weight) in the leaves and twigs of L. tridentata. Previously, NDGA has been shown to induce cystic nephropathy in the rat, however, no reports have been made concerning this compound's hepatotoxic potential. Here, we report that intraperitoneal adminstration of NDGA is lethal in the mouse (LD50=75mg/kg). Administration is associated with a time and dose-dependent increase in serum alanine aminotransferase levels, which suggest liver damage. Indeed, freshly isolated mouse hepatocytes are more sensitive to NDGA than human melanoma cells. Furthermore, we have identified glucuronidation as a potential detoxification mechanism for NDGA. Both mono and diglucuronide conjugates of NDGA are formed after intravenous dosing. The monoglucuronide is also formed after incubation of NDGA with human hepatic microsomes; suggesting that glucuronide conjugation is important in the metabolism of NDGA by humans. In summary, this report indicates that NDGA may contribute to the hepatotoxicity of L. tridentata and provides preliminary information on NDGA metabolism.

Original languageEnglish (US)
Pages (from-to)1701-1708
Number of pages8
JournalToxicon
Volume40
Issue number12
DOIs
StatePublished - Dec 1 2002

Fingerprint

Masoprocol
Detoxification
Larrea
Acids
Metabolism
Zygophyllaceae
Lignans
Liver
Lethal Dose 50
Glucuronides
Microsomes
Mexico
Alanine Transaminase
Rats
Hepatocytes
Melanoma

Keywords

  • Glucuronidation
  • Hepatotoxicity
  • Nordihydroguaiaretic Acid
  • Polyphenols

ASJC Scopus subject areas

  • Toxicology

Cite this

Lambert, J. D., Zhao, D., Meyers, R. O., Kuester, R. K., Timmermann, B. N., & Dorr, R. T. (2002). Nordihydroguaiaretic acid: Hepatotoxicity and detoxification in the mouse. Toxicon, 40(12), 1701-1708. https://doi.org/10.1016/S0041-0101(02)00203-9

Nordihydroguaiaretic acid : Hepatotoxicity and detoxification in the mouse. / Lambert, Joshua D.; Zhao, Dedun; Meyers, Ross O.; Kuester, Robert K.; Timmermann, Barbara N.; Dorr, Robert T.

In: Toxicon, Vol. 40, No. 12, 01.12.2002, p. 1701-1708.

Research output: Contribution to journalArticle

Lambert, JD, Zhao, D, Meyers, RO, Kuester, RK, Timmermann, BN & Dorr, RT 2002, 'Nordihydroguaiaretic acid: Hepatotoxicity and detoxification in the mouse', Toxicon, vol. 40, no. 12, pp. 1701-1708. https://doi.org/10.1016/S0041-0101(02)00203-9
Lambert JD, Zhao D, Meyers RO, Kuester RK, Timmermann BN, Dorr RT. Nordihydroguaiaretic acid: Hepatotoxicity and detoxification in the mouse. Toxicon. 2002 Dec 1;40(12):1701-1708. https://doi.org/10.1016/S0041-0101(02)00203-9
Lambert, Joshua D. ; Zhao, Dedun ; Meyers, Ross O. ; Kuester, Robert K. ; Timmermann, Barbara N. ; Dorr, Robert T. / Nordihydroguaiaretic acid : Hepatotoxicity and detoxification in the mouse. In: Toxicon. 2002 ; Vol. 40, No. 12. pp. 1701-1708.
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