Interindividual Variability in 2-Hydroxylation, 3-Sulfation, and 3-Glucuronidation of Ethynylestradiol in Human Liver(Biochemistry/Molecular Biology)
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概要
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In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of ethynylestradiol (EE_2) using human liver microsomes and cytosol. K_m values for the 2-hydroxylation and 3-glucuronidation in pooled liver microsomes and for the 3-sulfation in pooled liver cytosol were 3.34, 23.3, and 2.85 μM, respectively. V_<max>/K_m (ml/min/g liver) was highest for the 3-sulfation, followed by 2-hydroxylation, suggesting that 3-sulfation is the major metabolic pathway of EE_2 in human liver. All further studies were performed at a substrate concentration of 0.1 μM. Microsomal 2-hydroxylation and 3-glucuronidation activities ranged from 0.21 to 5.02 (2.04±1.34, mean±S.D., n=35) and 0.20 to 4.84 (1.20±1.00, n=35) pmol/min/mg protein, respectively. Cytosolic 3-sulfation activity ranged from 4.2 to 24.3 (11.8±4.4, n=21) pmol/min/mg protein. All the measured enzyme activities were neither gender-related nor age-dependent, except that 2-hydroxylation was significantly higher in females than in males (p<0.05). The relative contribution of CYP3A to the 2-hydroxylation in liver microsomes was estimated from the degree of inhibition by 1 μM ketoconazole. The degrees of inhibition were between 17.8 and 78.0% (51.6±16.0%, n=27). These results indicate that there are large interindividual differences in the enzyme activities towards the respective metabolic pathways of EE_2 and the relative contribution of CYP3A to the 2-hydroxylation of EE_2 in human liver.
- 公益社団法人日本薬学会の論文
- 2004-12-01
著者
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OHNO Yasuo
Division of Pharmacology, National Institute of Health Science
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Kawamura A
Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.:(present Address)analysis And
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Shirage Toshifumi
Departmnet Of Pharmacolinetics And Drug Metabolism Pharma Ceutical And Pharmacolinetic Research Labo
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Shiraga T
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Niwa T
近畿大学 薬学部
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Ohno Yasuo
国立医薬品食品衛生研究所
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NIWA Toshiro
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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SHIRAGA Toshifumi
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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KAGAYAMA Akira
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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Niwa T
Post-marketing Development Research Center Fujisawa Pharmaceutical Co. Ltd.
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Kagayama Akira
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Shiraga Toshifumi
Biopharmaceutical And Pharmacokinetic Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Ohno Yasuo
Division Of Internal Medicine And Thoracic Oncology National Cancer Center Hospital
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Niwa Toshiro
Post Marketing Product Development Astellas Pharma Inc.
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Kawamura Akio
Department Of Surgery Sapporo Hokuyu Hospital Research Institute For Artificial Organs Transplantati
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