1997 Fiscal Year Final Research Report Summary
Mechanism of molecular multiplicity and genetic deficiency of carbonyl reductase functioning as a drug-metabolizing enzyme
| Project/Area Number |
08672515
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Kumamoto University |
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Principal Investigator |
IMAMURA Yorishige Kumamoto University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (30040314)
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| Project Period (FY) |
1996 – 1997
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| Keywords | drug-metabolizing enzyme / molecular multiplicity / genetic deficiency / carbonyl reductase / rat liver microsomes / acetohexamide |
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| Research Abstract |
The mechanism of molecular multiplicity and genetic deficiency of carbonly reductase functioning as a drug-metabolizing enzyme has been examined. The obtained results are as follows :
1.An enzyme was partially purified from liver microsomes of male rats by using metyrapone as a substrate. The partially purified metyrapone reductase had no ability to reduce acetohexamide. These results indicate that the ketone-reduction of metyrapone and acetohexamide can be catalyzed by different carbonyl reductases.
2.1)A marked strain- and sex-related differences were observed in acetohexamide reductase activity in liver microsomes of rats. However, there was no strain- or sex-related difference of acetohexamide reductase activity in liver cytosol of rats. 2)Treatment with cadmium indirectly decreased acetohexamide reductase activity, which is regulated by androgens, in kidney microsomes of male rats. On the other hand, Cd treatment had no significant effect on acetohexamide reductase activity in kidney cytosol of male rats. The results described in 1)and 2)suggest multiplicity of carbonyl reductase present in rat liver and kidney.
3.A simple Mendelian genetic analysis for the frequency distribution of acetohexamide reductase activity in liver microsomes of male rats provides evidence that the phenotype is genetically regulated by an autosomal co-dominant fashion. Female rats, unlike male rats, did not exhibit microsomal enzyme activity in parental, first filial and second filial generations. Based on these results, it is concluded that the inheritance of the microsomal enzyme activity is sex-limited.
Further studies are in progress to elucidate the mechanism of genetic deficiency of acetohexamide reductase activity in liver microsomes of male rats.
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