Possible protective role of pregnenolone-16 alpha-carbonitrile in lithocholic acid-induced hepatotoxicity through enhanced hepatic lipogenesis.
Lithocholic acid (LCA) feeding causes both liver parenchymal and cholestatic damages in experimental animals. Although pregnenolone-16 alpha-carbonitrile (PCN)-mediated protection against LCA-induced hepatocyte injury may be explained by induction of drug metabolizing enzymes, the protection from the delayed cholestasis remains incompletely understood. Thus, the PCN-mediated protective mechanism has been studied from the point of modification of lipid metabolism. At an early stage of LCA feeding, an imbalance of biliary bile acid and phospholipid excretion was observed. Co-treatment with PCN reversed the increase in serum alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities and hepatic hydrophobic bile acid levels. LCA feeding decreased hepatic mRNA levels of several fatty acid- and phospholipid-related genes before elevation of serum ALT and ALP activities. On the other hand, PCN co-treatment reversed the decrease in the mRNA levels and hepatic levels of phospholipids, triglycerides and free fatty acids. PCN co-treatment also reversed the decrease in biliary phospholipid output in LCA-fed mice. Treatment with PCN alone increased hepatic phospholipid, triglyceride and free fatty acid concentrations. Hepatic fatty acid and phosphatidylcholine synthetic activities increased in mice treated with PCN alone or PCN and LCA, compared to control mice, whereas these activities decreased in LCA-fed mice. These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity.
Miyata
Masaaki
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp
Nomoto
Masahiro
M
Sotodate
Fumiaki
F
Mizuki
Tomohiro
T
Hori
Wataru
W
Nagayasu
Miho
M
Yokokawa
Shinya
S
Ninomiya
Shin-ichi
S
Yamazoe
Yasushi
Y
D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects*; D008095:Lithocholic Acid / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D013997:Time Factors
D015415:Biomarkers; D005227:Fatty Acids; D010713:Phosphatidylcholines; D011285:Pregnenolone Carbonitrile; D008095:Lithocholic Acid