Roles of human cytochrome P450 1A2 in coumarin 3,4-epoxidation mediated by untreated hepatocytes and by those metabolically inactivated with furafylline in previously transplanted chimeric mice
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- Miura Tomonori
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
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- Uehara Shotaro
- Laboratory Animal Research Department, Central Institute for Experimental Animals
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- Shimizu Makiko
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
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- Murayama Norie
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
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- Suemizu Hiroshi
- Laboratory Animal Research Department, Central Institute for Experimental Animals
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- Yamazaki Hiroshi
- Laboratory Animal Research Department, Central Institute for Experimental Animals
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Abstract
<p>Coumarin is a naturally occurring component of food products but is of clinical interest for its potential hepatotoxicity in humans. In the current study, the pharmacokinetics of coumarin in humanized-liver mice after oral and intravenous administrations (30 mg/kg) were investigated for its transformations to metabolically active coumarin 3,4-epoxide (as estimated by the levels of o-hydroxyphenylacetic acid) and to excretable 7-hydroxycoumarin. After oral administration, control mice metabolized coumarin to o-hydroxyphenylacetic acid at roughly the same rate as that to 7-hydroxycoumarin (total of unconjugated and conjugated forms). In contrast, the in vivo biotransformation of coumarin to o-hydroxyphenylacetic acid by humanized-liver mice was around two orders of magnitude less than that to conjugated and unconjugated 7-hydroxycoumarin. After intravenous administrations of coumarin, differences were observed in the plasma concentrations of o-hydroxyphenylacetic acid between humanized-liver mice treated with furafylline (daily oral doses of 13 mg/kg for 3 days) and untreated humanized-liver mice. The mean values of the areas under the plasma concentration versus time curves and the maximum concentrations for o-hydroxyphenylacetic acid were significantly lower in the group treated with furafylline (45% and 57% of the untreated values, respectively). These results suggested that the metabolic activation of coumarin in humans was mediated mainly by P450 1A2, which was suppressed by furafylline, and that humanized-liver mice orally treated with furafylline might constitute an in vivo model for metabolically inactivated P450 1A2 in human hepatocytes transplanted into chimeric mice.</p>
Journal
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- The Journal of Toxicological Sciences
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The Journal of Toxicological Sciences 46 (11), 525-530, 2021
The Japanese Society of Toxicology
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Keywords
Details 詳細情報について
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- CRID
- 1390571395580035840
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- NII Article ID
- 130008110376
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- NII Book ID
- AN00002808
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- ISSN
- 18803989
- 03881350
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- NDL BIB ID
- 031927576
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed