Binding of polynuclear aromatic hydrocarbons to the rat 4S cytosolic binding protein: Structure-activity relationships

The relative competitive binding affinites of benzo[a]pyrene (B[a]P), benzo[e]pyrene, benzo[g,h,i]perylene, picene, 7,12-dimethylbenz[a]anthracene, 1,2,3,4-dibenz[a]anthracene, 1,2,5,6-dibenz[a]anthracene, perylene, 4H-cyclopenta[d,e,f]-phenanthrene, benz[a]anthracene, triphenylethylene and triptycene for the rat hepatic cytosolic 4S binding protein were determined using [³H] benzo[a]pyrene as the radioligand. With the exception of triphenlethylene, triptycene and 4H-cycolopenta[d,e,f]phenanthrene, the EC₅₀ values for the remainder of these compounds were between 1.25 × 10^-7 and 2.5 × 10^-8 M with 1,2,5,6-dibenz[a]anthracene being the most active ligand. A comparison of the relative cytosolic Ah (9S) receptor binding affinities and aryl hydrocarbon hydroxylase (AHH) induction potencies of these hydrocarbons with their 4S protein binding affinities demonstrated the following: (a) five compounds, namely 1,2,5,6-dibenz[a]anthracene, 1,2,3,4-dibenz[a]anthracene, picene, benzo[a]pyrene and 3-methylcholanthrene exhibited high to moderate binding affinities for the 4S and 9S cytosolic proteins (EC₅₀ values < 10^-6 M) and induced AHH in rat hepatoma cells; (b) three compounds, namely perylene, benzo[e]pyrene and benzo[g,h,i]perylene exhibited high affinities for the 4S binding protein (1.25 × 10^-7, 4.4 × 10^-8 and 2.9 × 10^-8 M, respectively) and low affinities (EC₅₀ values 10^-5 M) for the Ah receptor protein; (c) moreover these three compounds did not induce AHH in rat hepatoma H-4-II E cells in culture. These data suggest that the 4S binding protein may not play a significant role in AHH induction although the results do not rule out a function for this protein in the transregulation of AHH and its associated cytochromes P-450.