Ozaki Hitomi, Sugihara Kazumi, Watanabe Yoko, Ohta Shigeru, Kitamura Shigeyuki
Graduate School of Biomedical and Health Sciences, Hiroshima University.
J Toxicol Sci. 2016;41(4):551-60. doi: 10.2131/jts.41.551.
The in vitro cytochrome P450 (CYP)-inhibitory effects of 11 parabens and 7 phthalates used in consumer products, as well as their hydrolytic metabolites, were investigated, using rat liver microsomes as an enzyme source. The effects on individual CYP isozymes were evaluated by assaying inhibition of activities towards specific substrates, i.e., ethoxyresorufin O-dealkylase (EROD), methoxyresorufin O-dealkylase (MROD), pentoxyresorufin O-dealkylase (PROD), 7-benzyloxy-4-trifluoromethylcoumarin dealkylase (BFCD), 7-methoxy-4-trifluoromethylcoumarin dealkylase (MFCD) and 7-ethoxy-4-trifluoromethylcoumarin dealkylase (EFCD) activities. These activities were dose-dependently inhibited, most potently by medium-side-chain parabens (C6-9) and phthalates (C4-6), and less potently by shorter- and longer-side-chain esters. The hydrolytic product of parabens, 4-hydroxybenzoic acid, was not inhibitory, while those of phthalates, phthalic acid monoesters, showed lower inhibitory activity than the parent phthalates. Parabens showed relatively potent inhibition of MFCD activity, considered to be mainly due to CYP2C, and phthalates showed relatively potent inhibition of PROD activity, considered to be mainly due to CYP2B.
以大鼠肝微粒体作为酶源，研究了消费品中使用的11种对羟基苯甲酸酯和7种邻苯二甲酸酯及其水解代谢产物的体外细胞色素P450（CYP）抑制作用。通过测定对特定底物的活性抑制来评估对各个CYP同工酶的影响，即乙氧基试卤灵O-脱烷基酶（EROD）、甲氧基试卤灵O-脱烷基酶（MROD）、戊氧基试卤灵O-脱烷基酶（PROD）、7-苄氧基-4-三氟甲基香豆素脱烷基酶（BFCD）、7-甲氧基-4-三氟甲基香豆素脱烷基酶（MFCD）和7-乙氧基-4-三氟甲基香豆素脱烷基酶（EFCD）活性。这些活性呈剂量依赖性抑制，中链对羟基苯甲酸酯（C6-9）和邻苯二甲酸酯（C4-6）的抑制作用最强，短链和长链酯的抑制作用较弱。对羟基苯甲酸酯的水解产物4-羟基苯甲酸没有抑制作用，而邻苯二甲酸酯的水解产物邻苯二甲酸单酯的抑制活性低于母体邻苯二甲酸酯。对羟基苯甲酸酯对MFCD活性表现出相对较强的抑制作用，认为主要是由于CYP2C；邻苯二甲酸酯对PROD活性表现出相对较强的抑制作用，认为主要是由于CYP2B。
