食量控制對Flutamide在大白鼠體內代謝的影響，並人體細胞色素及尿甘二磷酸葡萄糖醛酸轉化酵素對其羥基化及接合之研究   全文下載

Metabolism of Flutamide in Diet Control Fischer 344 and Brown Norway × F 344 Rats, and Its Hydroxylation and Conjugation by Human CYP450s and UDPGlucuronosyltransferases

使用flutamide 餵食大白鼠（Fscher 344, Brown Norway × F344），並加上食量控制。結果顯示食量控制可減少由flutamide 引起的細胞增生。在不限食量的F344 大白鼠實驗中，血液內flutamide 代謝產物（2-hydroxyflutamide）的含量為181 ± 26.6 ng／mL 。而在食量控制的大白鼠中，只有68 ± 8.0 ng／mL 。在Brown Norway × F344大白鼠中，也有同樣的效應（各為232 ± 57及52 ± 6.0 ng／mL）。在食量控制組中，肝細胞微體具較高之EROD 活性。BROD 則無明顯差異，大白鼠及人體肝細胞微體都有羥基化flutamide 為2-hydroxyflutamide 的功能。人體肝細胞微體之功能約為大白鼠肝細胞色素的十倍（0.673 ± 0.04對0.063 ± 0.008 nmol／min／mg 蛋白質）。其他人體細胞色素則不具此效應。人體淋巴細胞株培養的CYP1A1, 1A2, 2B1及2C19 亦有同樣的功能。人體的腎、肝及結腸細胞微體有接合2-hydroxyflutamide 的功能，腎細胞微體比肝及結腸細胞體的功能強。以人體尿甘二磷酸葡萄糖醛酸轉化酵素群（UGT 1A1, 1A4, 1A6, 1A7, 1A9,1A10）作2-hydroxyflutamide的接合研究，結果顯示UGT1A6 的效果最好。"

In our current report, flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl] propanamide) treated diet control and non limited-fed Fischer 344 (F344) and Brown Norway (BN) × F344 rats showed that diet control reduces spontaneous and flutamide-induced hyperplasia(1). In this continued study, we found that serum concentrations of active metabolite of flutamide, 2-hydroxyflutamide (OH-flu), were 181 ± 26.6 ng/mL and 68 ± 8.0 ng/mL (p<0.05), in non-limited fed and diet control F344 rats. In BN × F344 rats, the serum concentrations of 2-OH-flutamide were 232 ± 57 ng/mL and 52 ± 6 ng/mL (p<0.05) in non-limited fed and diet control animals. In diet control groups, liver microsomes from flutamide-treated F344 rats showed high 7-ethoxyresorufin O-deethylase (EROD) activity, while 7-Benzoxyresorufin O-dealkylase (BROD) activity was not affected significantly. Both rat and human liver microsomes showed flutamide oxidation activity. Human liver microsomes showed 10 times higher activity than rat liver microsomes (0.673 ± 0.04 vs 0.063 ± 0.008 nmol OH-flu/min/mg protein). Microsomes from human tissues such as colon, colon cancer, kidney, bladder, pancreas, prostate, prostate cancer, or ovarian cancer, showed no or non-detectable activity for flutamide hydroxylation. CYP450 1A1, 1A2, 1B1 and 2C19 from human lymphoblastoid cell lines, oxidized flutamide to OH-flu in vitro with activities from 0.118 ± 0.005 to 0.275 ± 0.010 nmol/min/mg protein. Microsomes isolated from human kidney, colon, and liver showed UDP-glucuronosyltransferase (UGT) activity for glucuronidation of OH-flu. Human kidney showed the highest activity. Several human recombinant UGTs (1A1, 1A4, 1A6, 1A7, 1A9, and 1A10) also showed glucuronidation activity for OH-flu. It was found that UGT1A6 was more active than other human UGTs. 使用flutamide 餵食大白鼠（Fscher 344, Brown Norway × F344），並加上食量控制。結果顯示食量控制可減少由flutamide 引起的細胞增生。在不限食量的F344 大白鼠實驗中，血液內flutamide 代謝產物（2-hydroxyflutamide）的含量為181 ± 26.6 ng／mL 。而在食量控制的大白鼠中，只有68 ± 8.0 ng／mL 。在Brown Norway × F344大白鼠中，也有同樣的效應（各為232 ± 57及52 ± 6.0 ng／mL）。在食量控制組中，肝細胞微體具較高之EROD 活性。BROD 則無明顯差異，大白鼠及人體肝細胞微體都有羥基化flutamide 為2-hydroxyflutamide 的功能。人體肝細胞微體之功能約為大白鼠肝細胞色素的十倍（0.673 ± 0.04對0.063 ± 0.008 nmol／min／mg 蛋白質）。其他人體細胞色素則不具此效應。人體淋巴細胞株培養的CYP1A1, 1A2, 2B1及2C19 亦有同樣的功能。人體的腎、肝及結腸細胞微體有接合2-hydroxyflutamide 的功能，腎細胞微體比肝及結腸細胞體的功能強。以人體尿甘二磷酸葡萄糖醛酸轉化酵素群（UGT 1A1, 1A4, 1A6, 1A7, 1A9,1A10）作2-hydroxyflutamide的接合研究，結果顯示UGT1A6 的效果最好。