Gene expression profile in liver of differing ages of rats after single oral administration of acetaminophen.
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 age-related 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.
Morishita
Katsumi
K
Toxicogenomics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
Mizukawa
Yumiko
Y
Kasahara
Toshihiko
T
Okuyama
Manabu
M
Takashima
Kayoko
K
Toritsuka
Naoki
N
Miyagishima
Toshikazu
T
Nagao
Taku
T
Urushidani
Tetsuro
T
D000082:Acetaminophen / Q000633:toxicity*; D000284:Administration, Oral; D000375:Aging / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D005978:Glutathione