Importance of peri-interactions on the stereospecificity of rat hydroxysteroid sulfotransferase STa with 1-arylethanols

Hydroxysteroid (alcohol) sulfotransferases catalyze the sulfation of polycy clic aromatic hydrocarbons (PAHs) that contain benzylic hydroxyl functional groups. This metabolic reaction is often a critical step in the activation of a hydroxyalkyl-substituted PAH to form an electrophilic metabolite that is capable of forming covalent bonds at nucleophilic sites on DNA, RNA, an d proteins, Since hydroxyalkyl-substituted PAHs are often metabolically for med by the stereoselective enzymatic hydroxylation of a benzylic position o n an alkyl-substituted PAH, we have investigated the possibility that the s ulfation of hydroxyalkyl aromatic hydrocarbons is also stereoselective, Hom ogeneous preparations of rat hepatic hydroxysteroid (alcohol) sulfotransfer ase STa were utilized to investigate the stereoselectivity of its catalytic function with the enantiomers of model 1-arylethanols. While only minimal stereoselectivity was observed for the catalytic efficiency of STa with the enantiomers of 1-(2-naphthyl)ethanol and 1-acenaphthenol, the enzyme was s tereospecific for (R)-(+)-1-( l-naphthyl)ethanol, (R)-(+)-1-(1-pyrenyl)etha nol, and (R)-(+)-1-(9-phenanthryl)ethanol as substrates. Moreover, (S)-(-)- 1-(I-naphthyl)ethanol (S)-(-)-1-(1-pyrenyl)ethanol, and (S)-(-)-1-(9-phenan thryl)ethanol were competitive inhibitors of STa. Structural and conformati onal analyses of these 1-arylethanols indicated that steric interactions be tween the substituents on the benzylic carbon and tho hydrogen in the peri- position on the aromatic ring system were important determinants of the ste reospecificity of the enzyme with these molecules. The findings presented h ere have implications for the more accurate prediction of the ability of hy droxyalkyl-substituted PAHs to be activated via metabolic formation of elec trophilic sulfuric acid eaters.