Interindividual variability in 2-hydroxylation, 3-sulfation, and 3-glucuronidation of ethynylestradiol in human liver.
In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of ethynylestradiol (EE2) using human liver microsomes and cytosol. Km 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 microM, respectively. Vmax/Km (ml/min/g liver) was highest for the 3-sulfation, followed by 2-hydroxylation, suggesting that 3-sulfation is the major metabolic pathway of EE2 in human liver. All further studies were performed at a substrate concentration of 0.1 microM. 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 microM 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 EE2 and the relative contribution of CYP3A to the 2-hydroxylation of EE2 in human liver.
Shiraga
Toshifumi
T
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan. toshifumi_shiraga@po.fujisawa.co.jp
Niwa
Toshiro
T
Ohno
Yasuo
Y
Kagayama
Akira
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D020719:Glucuronides / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013431:Sulfates / Q000378:metabolism
D020719:Glucuronides; D013431:Sulfates; C024860:ethinyl estradiol glucuronide; C025810:ethinylestradiol-3-sulfate; D004997:Ethinyl Estradiol