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

Abstract

1. The effects of some biodegradation products of 4-tert-octylphenol ethoxylate (OPEO), namely 4-tert-octylphenol (OP), 4-tert-octylphenol diethoxylate (OP2EO) and 4-tert-octylphenol monocarboxylate (OP1EC) on the kinetics of cytochrome P450 (P450) -dependent monooxygenases in rat liver microsomes have been studied. 2. Testosterone 16β-hydroxylase (TS16BH), testosterone 2α-hydroxylase (TS2AH) and testosterone 6β-hydroxylase (TS6BH) activities were extensively inhibited by OP at 100 μM (56.0-90.3%). Inhibition was competitive for all P450-dependent monooxygenases. K_is of TS16BH, TS2AH and TS6BH from Lineweaver-Burk plots were 6.37, 3.38 and 34.8 μM respectively. 3. The activities of acetanilide 4-hydroxylase(AA4H),7-ethoxycoumarin O-deethylase (ECOD) and bufuralol 1′-hydroxylase (BF1'H) were also effectively inhibited by OP at 100 μM (48.6-56.0%). The inhibition of these P450-dependent monooxygenases was non-competitive, and K_is (50.1-63.9 μM) were higher than those of TS16BH, TS2AH and TS6BH. 4. OP2EO also inhibited AA4H, ECOD, TS16BH, TS2AH, BF1'H and TS6BH activities by 38.7-69.3% at 100 μM, although the inhibition rates were slightly lower than those for OP. K_is were 14.4-106 μM, and the inhibition was of mixed type (AA4H and ECOD), competitive (TS16BH, TS2AH and TS6BH) and non-competitive (BF1'H). 5. Testosterone 7α-hydroxylase (TS7AH), 4-nitrophenol 2-hydroxylase (4NP2H) and lauric acid ω-hydroxylase (LAOH) activities were only slightly 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 μM. 7. These results suggest that OPEO biodegradation products interact with constitutive P450 isoforms, CYP1A2, CYP2A2, CYP2B2, CYP2C11 and CYP3A2 in rat liver in vitro (OP > OP2EO > OP1EC), and that the mechanism of this interaction differs depending on the compound and P450 isoform.