Influence of acetaminophen vehicle on regulation of transporter gene expression during hepatotoxicity.
Researchers who study acetaminophen (APAP) hepatotoxicity use either a 50% propylene glycol solution or saline as a diluent. Previous studies demonstrated differential expression of hepatobiliary transporter mRNA in mice treated with a toxic dose of APAP dissolved in 50% propylene glycol. The purpose of this study was to determine whether using saline as a diluent for APAP alters regulation of transporter gene expression during hepatotoxicity. Male C57BL/6J mice received acetaminophen (APAP 400 mg/kg, i.p. in saline) or saline (20 ml/kg). Plasma and liver samples were collected at 24 and 48 h for assessment of alanine aminotransferase (ALT) activity and gene expression. It was determined that plasma ALT activity was elevated at 24 and 48 h after APAP administration. Using the branched DNA signal amplification assay, reductions in organic anion-transporting polypeptides Oatp1a1, Oatp1b2, sodium/taurocholate-cotransporting polypeptide (Ntcp), and bile salt export pump (Bsep) mRNA were observed in APAP-treated mice. In contrast, multidrug resistance-associated proteins Mrp1, Mrp2, Mrp3, and Mrp4, as well as multidrug resistance proteins Mdr1a and Mdr1b genes, were increased following APAP. No changes in Oatp1a4, Mdr2, or breast cancer resistance protein (Bcrp) mRNA were observed. Alterations in transporter gene expression in this study were similar to those reported previously using propylene glycol as diluent. With the exceptions of Oatp1a1, Ntcp, and Mrp1, these data mirror previous results suggesting that the solution used to dissolve APAP may alter the susceptibility of mice to hepatotoxicity, but only minimally change the regulation of transporter gene expression.
Aleksunes
Lauren M
LM
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269-3092, USA.
Augustine
Lisa M
LM
Cherrington
Nathan J
NJ
Manautou
José E
JE
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014677:Pharmaceutical Vehicles / Q000494:pharmacology*; D019946:Propylene Glycol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D014677:Pharmaceutical Vehicles; D012333:RNA, Messenger; D000082:Acetaminophen; D012965:Sodium Chloride; D019946:Propylene Glycol; D000410:Alanine Transaminase