Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

Abstract

-In order to verify the influence of the rat age on hepatotoxicity, male Sprague-Dawley rats of 6 (young) and 12 (adult) weeks of age were orally administered acetaminophen (APAP), isoniazid (INH), or carbon tetrachloride (CCl4). Liver samples were obtained in a time-course manner, and changes in gene expression examined by an Affymetrix GeneChip. APAP caused more prominent hepatic injury with respect to pathology and blood biochemistry in adults than in young rats, whereas no obvious agerelated differences were observed in INH-or CCl4-treated rats. Comparing gene expression in control rats, CYP3A13 was higher and GSTY2c was lower in adults, suggesting that production of the active metabolite of APAP is higher and its detoxification is lower in adults. The total amount of glutathione and total SH in rat liver was found to be higher in adult rats whereas the extent of its reduction by APAP was larger in adults. A detailed analysis of genes showing age-related differences revealed that some of them were different not in their extent but in their time course, i.e., the stress responses occurred earlier in the young than in the adult, resulting in a difference at 24 hr after dosing. These results suggest that the age-related difference in toxicity would be attributed to a higher expression of CYP3A13, producing the active metabolite of APAP as well as the lower expression of the detoxification enzyme, GSTY2c, in adult rats. Furthermore, these differences affect the time course of APAP toxicity. The present study clearly depicts the advantage of the multi-time, multi-dose protocol employed in our project for analyzing the mechanism of toxicity by gene expression profiling.

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

“…19 This agreed with broad similarities with other drug toxicities. Characterization of liver injury in NOD/ SCID mice showed typical manifestations of ALF because of extensive hepatic necrosis, including abnormal liver test results, coagulopathy, and encephalopathy.…”

“…After Rif-Phen-MCT in NOD/SCID mice, Atm expression declined further, and greater perturbations in Atm signaling were observed in NOD/SCID mice with ALF. Examination of APAP-induced liver gene expression in an experimental study in rats, 19 in which gene expression was determined with limited probe sets 24 hours after APAP, showed 3-fold alterations in oxidative/metabolic stress genes (eg, heme oxygenase 1, Cyp7a1, flavin monooxygenase 1, Hspb1, Hspa8, and DnaJ) and in cell proliferation, growth arrest, and senescence genes (eg, Egr1, Ddit3, growth arrest and DNA damage-inducible 45␣, and Mdm2), which was similar to our results herein. These types of data should strengthen the role of Atm signaling in other forms of DILI; also, it should be appropriate to consider how regulation Previously, Atm Ϫ/Ϫ mice were shown to have impairment in liver regeneration, including mortality in some cases after partial hepatectomy.…”

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

“…increased Gadd153, Gadd45α, Hsp70, a Hsp 40-like EST and Jun (Table 3A). These changes were mainly detected at 24 h. This type of change was consistent with the previously reported in vivo effects of APAP in rats at a single dose (Morishita et al, 2006;Huang et al, 2004). Slightly increased p53 targets such as Gadd45α, Gadd153, Pcna (1.7-fold, data not shown) and Hsp27 (1.4-fold, data not shown) were observed at 24 h. On the other hand, other p53 targets such as Bax, cdkn1a and Ccng1 were not affected.…”

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

“…administration, although a potent increase of ALT and AST in 1,000 mg/kg to normal rats. The same single oral administration of APAP (1,000 mg/kg) with fasting condition was also adapted by the National Toxicogenomics project in Japan as the screening system, resulting in significant increase of ALT and AST at 24 h after treatment (37). However, there is no report about the effect of fasting on APAP hepatotoxicity.…”