Effects of acetaminophen on hepatic gene expression in mice.
Acetaminophen (APAP) is one of the most commonly used drugs for the safe and effective treatment of fever and pain. However, it is a well-established hepatotoxin. The objective of this study was to identify alternation in various genes in liver of mice after administration of low and high doses of APAP. Male C57BL/6J mice received APAP (30 or 300 mg/kg, i.p.). They were sacrificed after 6 hr and 24 hr for assessment of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total RNA isolation, cDNA microarray analysis and histopathological analysis of liver injury. Low dose of APAP did not cause hepatotoxicity in mice. However, it was toxic at a high dose. Using microarray technology, we selected changed genes more than 1.5 fold. Gene expression changes were recorded even at a low dose treatment with APAP. Six (6) hr after APAP treatment at low dose, 6 genes were up-regulated and 25 genes were down-regulated. However, 24 hr after treatment at low dose 8 genes were up-regulated and 34 genes were down-regulated. 6 hr after of high dose treatment 29 genes were down-regulated and none was up-regulated. A 24 hr treatment with high dose up-regulated 6 genes and down-regulated 18 genes. These expression patterns provide information on high versus low dose mechanisms of APAP toxicity. Gene expression signatures recorded after a nontoxic dose of APAP strongly support the validity of gene expression changes as meaningful markers of hepatotoxicity.
Jeong
Sun-Young
SY
Toxicogenomics Team, Korea Institute of Toxicology, 100 Jangdong, Yuseong, Daejeon, 305-343, Republic of Korea.
Lim
Jung-Sun
JS
Park
Han-Jin
HJ
Cho
Jae-Woo
JW
Rana
Suresh V S
SV
Yoon
Seokjoo
S
D000082:Acetaminophen / Q000494:pharmacology / Q000633:toxicity*; D000410:Alanine Transaminase / Q000235:genetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D000082:Acetaminophen; D012313:RNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase