Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats
Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity...
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| Format: | Article |
| Language: | English |
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Elsevier
2009-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319311168 |
| _version_ | 1818035142928629760 |
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| author | Sun J. Kim Min Y. Lee Do Y. Kwon Sung Y. Kim Young C. Kim |
| author_facet | Sun J. Kim Min Y. Lee Do Y. Kwon Sung Y. Kim Young C. Kim |
| author_sort | Sun J. Kim |
| collection | DOAJ |
| description | Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system. Keywords:: acetaminophen, metabolic activation, cytochrome P450 (CYP), reactive metabolite, hepatotoxicity |
| first_indexed | 2024-12-10T06:50:22Z |
| format | Article |
| id | doaj.art-b460624b6e4c4aafae1432869cff46ab |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-10T06:50:22Z |
| publishDate | 2009-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-b460624b6e4c4aafae1432869cff46ab2022-12-22T01:58:33ZengElsevierJournal of Pharmacological Sciences1347-86132009-01-011112175181Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in RatsSun J. Kim0Min Y. Lee1Do Y. Kwon2Sung Y. Kim3Young C. Kim4College of Pharmacy, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, KoreaCollege of Pharmacy, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, KoreaCollege of Pharmacy, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, KoreaCollege of Pharmacy, Wonkwang University, 344-2 Shinyong-Dong, Iksan 570-749, KoreaCollege of Pharmacy, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea; Corresponding author. youckim@snu.ac.krOur previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system. Keywords:: acetaminophen, metabolic activation, cytochrome P450 (CYP), reactive metabolite, hepatotoxicityhttp://www.sciencedirect.com/science/article/pii/S1347861319311168 |
| spellingShingle | Sun J. Kim Min Y. Lee Do Y. Kwon Sung Y. Kim Young C. Kim Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats Journal of Pharmacological Sciences |
| title | Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats |
| title_full | Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats |
| title_fullStr | Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats |
| title_full_unstemmed | Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats |
| title_short | Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats |
| title_sort | alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319311168 |
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