Defective Binding of 3-Methylcholanthrene to the Ah Roceptor witthin C3H/1OT1/2Clone 8 Mouse Fibroblasts in C

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Abstract
C3H/1OT1/2 clone 8 mouse fibroblasts (C3H/1OT1/2 cells) exhibit induction of aryl hydrocarbon hydroxylase (cytochrome P1‐450) when exposed in culture to benzo(a)pyrene, benz(a)anthracene or 2,3,7,8‐tetrachlorodibenzo‐P‐dioxin (TCDD), but do not display the induction response when treated with 3‐methylcholanthreme (MCA), the classical inducer of cytochrome P1‐450. Induction of cytochrome P1‐450. is regulated by the Ah receptor which initialy binds inducing chemicals in the cytoplasm, after which the inducer · receptor complex translocates into thenucleus. Cytosolic and nucloear forms of the Ahrecetor can be detected in C3H/1OT1/2 cells using [3H]TCDD as the radioligand in culture, but specific Ah receptor binding is not detectable within C3H/1OT1/2 cells incubated with [3H]MCA. In contrast, in Hepa‐1c1 cells, which exhibit cytochrome P1‐450 induction when trated with MCA. cytosolic and nuclear Ah receptor can be detected by incubation of the cells either with [3H]MCA or with [3H]TCDD. Nonradocative MCA is able to compete with [3J]TCDD for Ah receptor sites in C3H/1OT1/2 cells, but the relative potency of MCA as a competitor is lower within C3H/1OT1/2 cells than in C3H/1OT1/2 cytosol during extracellular incubation. Specific binding of [3H]MCA to Ah receptor can be detected by incubation of [3H]MCA with C3H/1OT1/2 cytosol outside the cell. The selective loss of response to MCA as cytochrome P1‐450 inducer (while retaining response to other inducers) appears tto be due to defective interaction of MCA with the Ah receptor within the intracellular environment. The specific molecualar alteraion whcih makes the MCA · receptor complex ineffective within C3H/1OT1/2 cell is unknown. Some fibroblast lines other than C3H/1OT1/2 also selectively fail to respond to MCA; thus, this variation in Ah receptor function may not be due to a mutational change in the Ah regulatory gene which codes for the Ah receptor.

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