Induction and inhibition of cytochrome P4501A in fish hepatoma cells exposed to halogenated aromatic hydrocarbons
- Woods Hole Oceanographic Institution, MA (United States). Biology Dept.
Induction of cytochrome P4501A (CYP1A)-dependent monooxygenase activities in cultured cells is being used to establish taxon-specific inducer structure-activity relationships (I-SAR) for planar halogenated aromatic hydrocarbons. Biphasic dose-response relationships and differences in maximal induction of catalytic activity are commonly seen in such studies, suggesting complex regulation of CYPLA, including partial agonism. The authors examined SAR for induction of CYPLA protein and catalytic function in PLHC-1 fish hepatoma cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran (TCDF), and four planar chlorobiphenyl (PCB) congeners. Induction of ethoxyresorufin O-deethylase (EROD) activity was biphasic, with stronger induction at lower concentrations and an attenuated response at higher concentrations. The compounds differed in potency and in the maximal EROD rates induced. In contrast, immunodetectable CYPLA protein increased monotonically with dose and achieved similar maxima for all six compounds. TCDF and 3,3{prime},4,4{prime}-TCB were competitive inhibitors of EROD activity in fish hepatic microsomes, suggesting a mechanism for the biphasic EROD response. Three ortho-substituted PCBs that induce CYPLA in mammals were inactive as inducers of CYPLA in PLHC-1 cells, indicating phylogenetic differences in I-SAR. These results highlight the need for complementary measures of CYPLA induction.
- OSTI ID:
- 42910
- Report Number(s):
- CONF-9410273--
- Country of Publication:
- United States
- Language:
- English
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