Inhibition of rat hepatic cytochrome P450 activities by biodegradation products of 4-tert-octylphenol ethoxylate

1. The effects of some biodegradation products of 4-tert-octylphenol ethoxy late (OPEO), namely 4-tert-octylphenol (OP), 4-tert-octylphenol diethoxylat e (OP2EO) and 4-tert-octylphenol monocarboxylate (OP1EC) on the kinetics of cytochrome P450 (P450)-dependent monooxygenases in rat liver microsomes ha ve been studied. 2. Testosterone 16 beta-hydroxylase (TS16BH), testosterone Za-hydroxylase ( TS2AH) and testosterone 6 beta-hydroxylase (TS6BH) activities were extensiv ely inhibited by OP at 100 mu M (56.0-90.3 %). Inhibition was competitive f or all P450-dependent monooxygenases. K(i)s of TS16BH, TS2AH and TS6BH from Lineweaver-Burk plots were 6.37, 3.38 and 34.8 mu M respectively. 3. The activities of acetanilide 4-hydroxylase (AA4H), 7-ethoxycoumarin O-d eethylase (ECOD) and bufuralol 1'-hydroxylase (BF1'H) were also effectively inhibited by OP at 100 mu M (48.6-56.0%). The inhibition of these P450-dep endent monooxygenases was non-competitive, and K(i)s (50.1-63.9 mu M) were higher than those of TS16BH, TS2AH and TS6BH. 4. OP2EO also inhibited AA4H, ECOD, TS16BH, TS2AH, BF1'H and TS6BH activiti es by 38.7-69.3 % at 100 mu M, although the inhibition rates were slightly lower than those for OP. K(i)s were 14.4-106 mu M, and the inhibition was o f mixed type (AA4H and ECOD), competitive (TS16BH, TS2AH and TS6BH) and non -competitive (BF1'H). 5. Testosterone 7 alpha-hydroxylase (TS7AH), 4-nitrophenol 2-hydroxylase (4 NP2H) and lauric acid omega-hydroxylase (LAOH) activities were only slightl y affected by OP and OP2EO. 6. The ability of OP1EC to inhibit P450-dependent monooxygenase activities was generally weaker than that of OP and of OP2EO: K-i > 200 mu M. 7. These results suggest that OPEC biodegradation products interact with co nstitutive P450 isoforms, CYP1A2, CYP2A2, CYP2B2, CYP2C11 and CYP3A2 in rat liver in vitro (OP > OP2EO > OP1EC), and that the mechanism of this intera ction differs depending on the compound and P450 isoform.