title: Metabolic adaptive ALT isoenzyme response in livers of C57/BL6 mice treated with dexamethasone.
abstract: Alanine aminotransferase (ALT) is used as an indicator of hepatocellular injury. Since ALT consists of two isoenzymes, a better understanding of ALT isoenzyme biology in response to compounds that cause metabolic adaptive versus hepatotoxic responses will allow for a more accurate assessment of the significance of an ALT increase. The purpose of this study was to characterize the ALT isoenzyme response in mice treated with 25 or 75 mg/kg of dexamethasone, which is known to induce a progluconeogenic state, for 24 or 72 hr. Those mice treated with 75 mg/kg for 72 hr showed an increase in total liver ALT activity. Western blot showed that there was an increase in ALT2 at both doses and time points and there was a concurrent increase in ALT2 ribonucleic acid at 24 and 72 hr. The ALT isoenzyme response assessed by an activity assay showed an increase in ALT2. The increases in liver ALT were associated with an increase in liver glycogen and there was no hepatocellular necrosis. There was an increase in total serum ALT activity, although serum isoenzymes were not evaluated. Thus, the authors demonstrated that dexamethasone induced increases in hepatic and serum ALT, which reflect a hepatocellular progluconeogenic metabolic adaptive response.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, Eastern Point Rd., MS 274/1203, Groton, CT 06340, USA. william.j.reagan@pfizer.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Reagan
authors.forename: Rong-Ze
authors.initials: RZ
authors.lastname: Yang
authors.forename: Soohyun
authors.initials: S
authors.lastname: Park
authors.forename: Richard
authors.initials: R
authors.lastname: Goldstein
authors.forename: Dominique
authors.initials: D
authors.lastname: Brees
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Gong
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects*; D000410:Alanine Transaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity*; D006003:Glycogen / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007527:Isoenzymes; D012333:RNA, Messenger; D003907:Dexamethasone; D006003:Glycogen; D000410:Alanine Transaminase