Phytol-induced hepatotoxicity in mice.
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 alpha (PPARalpha) 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 PPARalpha-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.
Mackie
John T
JT
Department of Pathobiology, Texas A&M University, TVMC, College Station, Texas, USA. john-mackie@idexx.com
Atshaves
Barbara P
BP
Payne
H Ross
HR
McIntosh
Avery L
AL
Schroeder
Friedhelm
F
Kier
Ann B
AB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism / Q000592:standards; D005260:Female; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009336:Necrosis / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism; D010831:Phytanic Acid / Q000378:metabolism / Q000592:standards; D010836:Phytol / Q000008:administration & dosage / Q000494:pharmacology*; D012015:Reference Standards; D012737:Sex Factors; D013997:Time Factors
D002352:Carrier Proteins; D005227:Fatty Acids; D047493:PPAR alpha; C072087:sterol carrier proteins; D010831:Phytanic Acid; D010836:Phytol; C002844:pristanic acid