| Budget Amount *help |
¥3,710,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Pyrethroid insecticides are commonly used for both household and agricultural applications. To examine the role of human carboxylesterase (CES) isozymes in pyrethroid hydrolysis, we cloned the cDNAs encoding human CES1, CES2 and CES3, and expressed in HEK293 cells and characterized their hydrolytic activities.
We found that recombinant human CES1 and CES2 could hydrolyze permethrin, one of the representative type I pyrethroid, whereas, we could not detect any permethrin hydrolytic activity of CES3. These findings indicate that CES1 and CES2 play an important role in the degradation of pyrethroid insecticides in human tissues.
It has been shown that variations in the hydrolytic rates toward permethrin were observed in human liver samples. In the present study, wild-type (WT) and variant (S75N, G188R, R199H and D203E) CES1 proteins were expressed in HEK293 cells for functional characterization. WT and variant CES1s, S75N, R199H and D203E, catalyzed permethrin hydrolysis with almost similar
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apparent Km values and Vmax values. However, the hydrolysis activity of G188R was less than 5% of the wild-type CES1. These results clearly indicate that the G188R variant is essentially nonfunctional with regard to permethrin hydrolysis. These findings indicate that genetic polymorphism, G188R, could contribute to interindividual variability in metabolism of pyrethroid insecticides in human liver.
Profluthrin, one of the highly-volatile pyrethroids insecticides, is recently used for household applications. To examine the role of human CES isozymes in profluthrin hydrolysis, we characterized their hydrolytic activities. We found that recombinant human CES1 and CES2 (CES1>>CES2) can hydrolyze profluthrin, whereas, we could not detect any hydrolytic activity for CES3. It was reported that tissue specific expression of CES1 and CES2, CES1 was highly expressed in liver and lung, CES2 was highly expressed in small intestine, kidney and skin. To clarify these substrate structure-activity relationships and the tissue distribution of CES isozymes is critical for predicting the metabolism and the pharmacokinetics of pyrethroid insecticides. Less
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