CORRELATION BETWEEN MURINE LIVER CYTOCHROME-P450 2B1 INDUCTION BY HALOGENATED HYDROCARBONS AND TOXICITY

The aim of this investigation was to study the relationship between th e induction of cytochrome P450 2B1 isozymes by thirteen halogenated hy drocarbons and their toxicity. Each chemical, 1,1,2,2-tetrabromoethane (1,1,2,2-TBE), 1,1,1,2-tetrachloroethane (1,1,1,2-TCE), 1,1,2,2,-tetr achloroethane (1,1,2,2-TCE), pentachloroethane (PCE), 1,2-dibromoethan e (1,2-DBE), iodoethane (IE), 1,1-dichloroethane (1,1-DCE), 1,2-dichlo roethane (1,2-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-D CEE) and trans 1,2-dichloroethylene (t 1,2-DCE) was administered (i.p. ) in a dose-response fashion (from 50 to 6.25% of the respective LD(50 )) for three consecutive days, to Swiss Albino CD1 mice and the dealky lation of pentoxyresonrufin examined in hepatic microsomes as 2B1 prob e. For each hydrocarbon, linear regression was performed for both the inductive and toxic slope related to 2B1-like activity in order to eva luate the IC100 [the dose, in mmol/kg, producing a 100% increase of pe ntoxyresorufin dealkylation (PROD) during the induction phase] and the TC100 (the dose producing the same percental induction but during the toxic phase). The 1,1-DCEE was the only chemical which failed to indu ce Cyp2B1 gene as immunochemically demonstrated by Western blot analys is, using rabbit polyclonal antibody anti-P450 2B1 subfamily. The calc ulated regression coefficients were: 0.78 (n = 12) between log 1/TC100 vs log 1/IC100, 0.81 (n = 12) between log 1/LD(50) vs log 1/IC100 and 0.93 (n = 12) between log 1/LD(50) vs log 1/TC100. This data provided additional support for the correlation between induction of Cyp2B1 (i .e. PROD induction potencies of specific halogenated hydrocarbons) and their relative toxicities (see the preceding paper, on this issue).