Regioselectivity of rat liver microsomal UDP-glucuronosyltransferase activities toward phenols of benzo(a)pyrene and dibenz(a,h)anthracene.

Inducibility of rat liver microsomal UDP-glucuronosyltransferase was investigated with regard to the substrate structure using 3-, 6-, 7-, 8-, and 9-hydroxybenzo(a)pyrene, all seven phenols of dibenz(a,h)anthracene, 3-hydroxybenz(a)anthracene, and 3-hydroxyfluoranthene as substrates. Glucuronide formation of the majority of the planar phenols was preferentially inducible by 3-methylcholanthrene (4- to 8-fold, group 1). However, glucuronidation of 8-hydroxybenzo(a)pyrene, 3-hydroxybenz(a)anthracene, and 3-hydroxydibenz(a,h)anthracene was markedly inducible by phenobarbital (3- to 8-fold, group 2). Glucuronidation of 9-hydroxybenzo(a)pyrene and 3-hydroxyfluoranthene was only moderately induced by the two inducers (less than 2-fold, group 3). Glucuronidation was also determined with purified phenol UDP-glucuronosyltransferase from 3-methylcholanthrene-treated rats. A close correlation (r = 0.95) was observed between purification factors (ratio of enzyme activities in purified enzyme and microsomes) and induction factors (ratio of microsomal enzyme activities from 3-methylcholanthrene-treated rats and untreated controls). Interestingly, differences in size and shape of group 1 and 2 substrates could be recognized. Group 1 substrates were shorter (less than 1.3 nm) and broader (greater than 1.1 nm) than group 2 substrates when viewed from the hydroxy group, along the axis of the C-O bond, to the plane of the polycyclic aromatic hydrocarbon, suggesting a distinct geometry of the binding site of the 3-methylcholanthrene-inducible phenol UDP-glucuronosyltransferase.