This Article Free Full Text Free Free Full Text (Free PDF) Free All Versions of this Article: 0192623308330789v1 37/2/201    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Mackie, J. T. Articles by Kier, A. B. Search for Related Content PubMed PubMed Citation Articles by Mackie, J. T. Articles by Kier, A. B. Social Bookmarking                         What's this?

Phytol-induced Hepatotoxicity in Mice

¹ Department of Pathobiology, Texas A&M University, TVMC, College Station, Texas, USA
² Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, Texas, USA

Correspondence: John T. Mackie, IDEXX Laboratories, 3 Overend Street, East Brisbane, Queensland 4169, Australia; e-mail:john-mackie{at}idexx.com.

Phytanic acid is a branched-chain, saturated fatty acid present in high concentrations in dairy products and ruminant fat. Some other dietary fats contain lower levels of phytol, which is readily converted to phytanic acid after absorption. Phytanic acid is a peroxisome proliferator binding the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) to induce expression of genes encoding enzymes of fatty acid oxidation in peroxisomes and mitochondria. Administration of dietary phytol (0.5% or 1%) to normal mice for twelve to eighteen days caused consistent PPAR-mediated responses, such as lower body weights, higher liver weights, peroxisome proliferation, increased catalase expression, and hepatocellular hypertrophy and hyperplasia. Female mice fed 0.5% phytol and male and female mice fed 1% phytol exhibited midzonal hepatocellular necrosis, periportal hepatocellular fatty vacuolation, and corresponding increases in liver levels of the phytol metabolites phytanic acid and pristanic acid. Hepatic expression of sterol carrier protein-x (SCP-x) was five- to twelve-fold lower in female mice than in male mice. These results suggest that phytol may cause selective midzonal hepatocellular necrosis in mice, an uncommon pattern of hepatotoxic injury, and that the greater susceptibility of female mice may reflect a lower capacity to oxidize phytanic acid because of their intrinsically lower hepatic expression of SCP-x.

Key Words: phytol • phytanic acid • PPAR • SCP-x • peroxisomes • fatty acids

Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase • PCNA, proliferating cell nuclear antigen • PPAR, peroxisome proliferator-activated receptor • SCP-x, sterol carrier protein-x

This version was published on February 1, 2009

Toxicologic Pathology, Vol. 37, No. 2, 201-208 (2009)
DOI: 10.1177/0192623308330789


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?