Biological and Pharmaceutical Bulletin p. 1060 - 1065 (1995)
Update date:2022-08-11
Topics:
Narimatsu
Tachibana
Masubuchi
Imaoka
Funae
Suzuki
Alprenolol 4-hydroxylation and N-desisopropylation in liver microsomes from male Wistar rats were kinetically analyzed to be biphasic. In the 4- hydroxylation at a low substrate concentration (5 μM), significant strain [Wistar > Dark Agouti (DA)] and sex (male > female) differences were observed, and the differences decreased at a high substrate concentration (1 mM). In the N-desisopropylation, only a strain difference (Wistar > DA) was observed at the low substrate concentration. Cytochrome P450BTL (P450BTL, corresponding to CYP2D2) in a reconstituted system with 5 μM alprenolol had high 4-hydroxylase activity, which was about 10 times that of P450ml corresponding to CYP2C11, and N-desisopropylase activity at a similar extent to P450ml. The two microsomal activities at 5 μM alprenolol were efficiently decreased by antibodies against P450BTL and by sparteine, a typical substrate of the CYP2D subfamily. Polyclonal antibodies against P450ml and P450PB-1 (corresponding to CYP3A2) partially suppressed only N-desalkylation at 5 μM, whereas they reduced the two activities at 1 mM. P450ml showed a high N- desisopropylase activity at a substrate concentration of 1 mM, where the sex difference was not observed. Furthermore, P450PB-2 corresponding to CYP2C6, which is one of the major P450 isozymes in female rats, also had 4- hydroxylase and N-desalkylase activities. These results suggest that a CYP2D isozyme(s) is the primary enzyme in alprenolol 4-hydroxylation and N- desisopropylation in a lower substrate concentration range, and that the involvement of some male-specific P450 isozyme(s) other than CYP2C11 or CYP3A2 may cause the sex difference in the 4-hydroxylation. In a higher substrate concentration range, CYP2C11 is thought to play a major role particularly in N-desisopropylation in male rats. In female rats, some major constitutive P450 isozyme(s) with a relatively high K(m) value (e.g., CYP2C6) may be involved in the metabolism of alprenolol, resulting in the disappearance of the sex difference.
View MoreBrightGene Bio-Medical Technology Co., Ltd.
website:https://en.bright-gene.com/
Contact:+86-512-62551801
Address:Building C25 - C31, No. 218 Xinghu Road, Suzhou Industrial Park, Suzhou, Jiangsu, China.
Xi'an North Information Industry Co., Ltd. Weilv Chemical Department
Contact:+86-29-88156413
Address:Jixiang Road 99 Xi'an Shaanxi Province
SHIFANG SUHONG CHEMICAL CO.,LTD
Contact:+86-838-2224563
Address:Room 1207 Zongchen Sunshine No.128 Taishan South Road,Deyang City,Sichuan China
ZHEJIANG JIANYE CHEMICAL CO.,LTD.
Contact:86-571-64149273,64149234
Address:No. 48, Fuxi Road, Meicheng Town
Nanjing Spring & Autumn Biological Engineering Co., Ltd.
Contact:86-180510-83338
Address:Suite# 210, No. 1 BuildingNanjing Agricultural Biotechnology High-tech Entrepreneurship Center, No. 4 Tongwei Road, Xuanwu District, Nanjing,China
Doi:10.1016/j.cclet.2012.01.021
(2012)Doi:10.1016/j.tetlet.2012.10.132
(2013)Doi:10.1021/ja01513a003
(1959)Doi:10.1016/S0040-4039(02)01276-5
(2002)Doi:10.1002/hlca.19930760431
(1993)Doi:10.1016/j.apcata.2014.04.031
(2014)