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 ethoxylate (OPEO), namely 4-tert-octylphenol (OP), 4-tert-octylphenol diethoxylate (OP2EO) and 4-tert-octylphenol monocarboxylate (OPIEC) on the kinetics of cytochrome P450 (P450) -dependent monooxygenases in rat liver microsomes have been studied. 2. Testosterone 16beta-hydroxylase (TS16BH), testosterone 2alpha-hydroxylase (TS2AH) and testosterone 6beta-hydroxylase (TS6BH) activities were extensively inhibited by OP at 100 microM (56.0-90.3%). Inhibition was competitive for all P450-dependent monooxygenases. Ki(s) of TS16BH, TS2AH and TS6BH from Lineweaver-Burk plots were 6.37, 3.38 and 34.8 microM 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 microM (48.6-56.0%). The inhibition of these P450-dependent monooxygenases was non-competitive, and Ki(s) (50.1-63.90 microM) 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 microM, although the inhibition rates were slightly lower than those for OP. K(i)s were 14.4-106 microM, and the inhibition was of mixed type (AA4H and ECOD), competitive (TS16BH, TS2AH and TS6BH) and non-competitive (BF1'H). 5. Testosterone 7alpha-hydroxylase (TS7AH), 4-nitrophenol 2-hydroxylase (4NP2H) and lauric acid omega-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: Ki >200 microM. 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.
Hanioka
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Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan. hanioka@nihs.go.jp
Jinno
H
H
Chung
Tanaka-Kagawa
T
T
Nishimura
T
T
Ando
M
M
D015660:7-Alkoxycoumarin O-Dealkylase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001673:Biodegradation, Environmental; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C025619:steroid 16-beta-hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; C105260:4-tert-octylphenol