The induction by monochlorodibenzofuran isomers of xenobiotic metabolizing systems in cell lines derived from rat and human hepatoma.
Cultures of established cell lines, derived from rat and human hepatomas, were exposed to dibenzofuran (DBF) or monochlorodibenzofuran isomers (Cl-DBFs) and the induction of cytochrome P-450-dependent monooxygenases was examined. When rat (H4-II-E-C3) cell cultures were incubated with 2-Cl- or 3-Cl-DBF, the activities of arylhydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase increased progressively and after 20 hr of incubation reached a maximum, while benzphetamine N-demethylase activity was scarcely induced. The maximum AHH activities were 15.1 and 7.9 times the initial values, after incubation with 3-Cl- and 2-Cl-DBFs, respectively. DBF also increased AHH activity, to a maximum, 2.7 times the initial activity, after 14 hr of incubation. Similar results were obtained when human (Chang liver) cell cultures were incubated with DBF, 2-Cl- or 3-Cl-DBF. To determine relative induction potencies, rat cell cultures were incubated with 25-150 μm of 1-Cl-, 2-Cl-, 3-Cl- or 4-Cl-DBF for 20 hr. Both the AHH and 7-ethoxycoumarin O-deethylase activities were increased in a dose-dependent manner by 2-Cl-, 3-Cl- and 4-Cl-DBF (in the order 3-Cl- > 2-Cl- = 4-Cl-). The immunoreactive cytochrome P-450c of rat cells was similarly increased by incubation with 2-Cl-, 3-Cl or 4-Cl-DBF (3-Cl- > 2-Cl- = 4-Cl-). 1-Cl-DBF increased neither AHH activity nor cytochrome P-450c. These results indicate that isomers of Cl-DBFs induce effectively 3-methylcholanthrene-inducible type of cytochrome P-450.
Miura
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T
Basic Medical Sciences Division, The National Institute for Environmental Studies, 16-2, Onogawa, Tsukuba, Ibaraki 305, Japan.
Takahashi
Y
Y