Dock L, Waern F, Martinez M, Grover P L, Jernstrom B
Chem Biol Interact. 1986 Jun;58(3):301-18. doi: 10.1016/s0009-2797(86)80105-3.
The syn- and anti-diastereoisomers of trans-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) were further metabolized by rat liver microsomes obtained from 3-methylcholanthrene(MC)-pretreated rats and NADPH to reactive intermediates, presumably 1,7,8- and 3,7,8-trihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrenes (triol-epoxides), that bound to macromolecules or decomposed to products consistent with pentahydroxy derivatives of benzo[a]pyrene (BP-pentols). Three major metabolites of syn-BPDE and four major metabolites of anti-BPDE were isolated by high performance liquid chromatography and characterized by spectroscopic techniques. When fluorescence spectroscopy was employed all metabolites exhibited very similar spectral properties and showed substantial shifts in excitation and emission maxima to longer wavelengths when measured under alkaline conditions, consistent with the presence of a phenolic hydroxyl group. Furthermore, the spectral properties of the metabolites from syn- and anti-BPDE were similar to those of 1-hydroxypyrene. Previous data from this laboratory together with the data presented in this study thus strongly suggest that further metabolism of BPDE involves hydroxylation at the 1- and 3-positions to yield the corresponding triol-epoxides and various BP-pentols. The pentols could also be formed by incubating tetrols derived from syn- and anti-BPDE with microsomes and NADPH. However, the rate of formation of pentols from the BP-tetrols was much slower than the rate of further metabolism of BPDE. Accordingly, the major route of BP-pentol formation is likely to be via the intermediate formation of triol-epoxides. Isolated liver nuclei from MC-pretreated rats were also found to catalyze the activation of anti-BPDE in presence of NADPH to reactive intermediates. This resulted in a substantial increase in binding to histone and non-histone proteins, with a concomitant decrease in binding to DNA. No qualitative change in the distribution of DNA-bound products of anti-BPDE could be demonstrated as a result of the further metabolism of anti-BPDE.
