Correlation between murine liver cytochrome p450 2b1 induction by halogenated hydrocarbons and toxicity

The aim of this investigation was to study the relationship between the induction of cytochrome P450 2B1 isozymes by thirteen halogenated hydrocarbons 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,‐tetrachloroethane (1,1,2,2‐TCE), pentachloroethane (PCE), 1,2‐dibromoethane (1,2‐DBE), iodoethane (IE), 1, 1‐dichloroethane (1,1‐DCE), 1,2‐dichloroethane (1,2‐DCE), 1,1,1‐trichloroethane (1,1,1‐TCE), 1,1,2‐trichloroethane (1,1,2‐TCE), dichloromethane (DCM), 1,1‐dichloroethylene (1,1‐DCEE) 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 LD₅₀) for three consecutive days, to Swiss Albino CD1 mice and the dealkylation of pentoxyresorufin examined in hepatic microsomes as 2B1 probe. For each hydrocarbon, linear regression was performed for both the inductive and toxic slope related to 2Bl‐like activity in order to evaluate the IC₁₀₀ [the dose, in mmol/kg, producing a 100% increase of pentoxyresorufin 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 induce Cyp2Bl gene as immunochemically demonstrated by Western blot analysis, using rabbit polyclonal antibody anti‐P450 2B1 subfamily. The calculated regression coefficients were: 0.78 (n = 12) between log 1/TC₁₀₀ vs log 1/IC₁₀₀, 0.81 (n = 12) between log 1/LD₅₀ vs log 1/IC₁₀₀ and 0.93 (n = 12) between log l/LD₅₀ vs log 1/TC₁₀₀. This data provided additional support for the correlation between induction of Cyp2Bl (i.e. PROD induction potencies of specific halogenated hydrocarbons) and their relative toxicities (see the preceding paper, on this issue).

Key words:

• Halogenated hydrocarbons
• monooxygenases
• cytochrome P450
• toxicity
• induction