Selective induction of murine liver cytochrome p450 IIB1 by Halogenated hydrocarbons

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Abstract
Thirteen halogenated hydrocarbons, 1,1,1,2‐tetrachloroethane (1,1,1,2‐TCE), 1,1,2,2‐tetrachloroethane (1,1,2,2‐TCE), pentachloroethane (PCE), 1,2‐dibromoethane (DBE), 1,1,2,2‐tetrabromoethane (1,1,2,2‐TBE), iodoethane (IE), 1,1‐dichloroethane (1,1‐DCE), 1,1,1‐trichloroethane (1,1,1‐TCE), 1,1,2‐trichloro‐ethane (1,1,2‐TCE), dichloromethane (DCM), 1,1‐dichloroethylene (1,1‐DCEE) and trans 1,2‐dichloro‐ethylene (t1,2‐DCE) were evaluated for their ability to modulate specific cytochrome P450 (cyt P450) isoforms following in vivo administration in male mice. Each chemical was administered (i.p.) in equivalent doses (50, 25, 12.5 and 6.25% of the respective LD50). Total cyt P450 and selected microsomal monoxygenase activities towards different P450 isoenzymes (classes IA1, UBI, IIE1 and IIIA P450) were examined in hepatic microsomes. With the exception of 1,1‐DCE, all considered hydrocarbons were inducers of Cyp2B1 genes, as exemplified by the enhancement of pentoxyresorufin O‐dealkylation. A 1.5‐(DBE, DCM) to 6‐fold (1,1,2,2‐TCE, 1,1‐DCE) induction of this IIB1‐dependent activity, was recorded. The ranking of relative induction potency was 1,1,2,2‐TCE ≍ 1,1‐DCE > 1,1,1‐TCE > 1,2‐DCE > 1,1,1,2‐TCE > PCE > IE > 1,1,2,2‐TBE > t 1,2‐DCE > 1,1,2‐TCE > DCM > 1,2‐DBE. In PCE‐, and to a lesser extend in IE‐ and 1,1,1‐TCE‐intoxicated mice, an increase (up to 6‐fold at the highest PCE dose) of ethoxyresorufin O‐deethylase activity (IA1) was also achieved. Cyt P450 was increased up to 2.8‐fold (PCE, 1,1‐DCE, DCM, t 1,2‐DCE), decreased up to 0.6‐fold (DBE, 1,2‐DCE, 1,1,2‐TCE, 1,1‐DCEE) or both (1,1,2,2‐TCE, 1,1,1‐TCE). The other monooxygenases were reduced to various degrees as it was expected by the well‐known toxic nature of these compounds. Increases of cyt P450IIB1 levels, determined by western immunoblotting analysis using rabbit polyclonal antibody anti‐P450 IIB1 subfamily, closely paralleled those observed with the marker catalytic activity. The data provide evidence for the possible cotoxic, comutagenic/cocarcinogenic, carcinogenic and promoting properties of these chemicals.

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