Regioselective and stereoselective metabolisms of pyrene and 1-bromopyrene by rat liver microsomes and effects of enzyme inducers.
Due to the symmetrical property of pyrene (Py), trans-dihydrodiols formed at 4,5- and 9,10-positions are identical, as are the monohydroxylated products (phenols) formed at C1, C3, C6, and C8 positions. With a bromo substituent at C1 position of Py, 1-bromopyrene (1-BrPy) trans-4,5-dihydrodiol and 1-BrPy trans-9,10-dihydrodiol are distinctly different products, as are the phenolic products formed at C3, C6, and C8 positions. Products formed in the oxidative metabolism of 1-BrPy by rat liver microsomes were characterized by retention times on reversed-phase high performance liquid chromatography (HPLC), and by ultraviolet-visible absorption and mass spectral analyses. We have compared regioselective and stereoselective metabolisms at the K- and non-K-regions of Py and 1-BrPy by liver microsomes from untreated (control), phenobarbital (PB)-treated, 3-methylcholanthrene (MC)-treated, and polychlorinated biphenyls (PCB, Aroclor 1254)-treated rats. The effects of inducers on the relative amounts of non-K-region phenols formed in the metabolisms of Py and 1-BrPy by rat liver microsomes were: MC greater than PCB greater than PB greater than control. The relative order was PB greater than PCB greater than MC greater than control for the formation of both 1-BrPy trans-4,5-dihydrodiol and 1-BrPy trans-9,10-dihydrodiol in the metabolism of 1-BrPy. The ratios between metabolically formed 1-BrPy trans-4,5-dihydrodiol to Py trans-4,5-dihydrodiol, using 0.5 mg of microsomal protein per ml of incubation mixture, were between 0.4 and 0.6 in the presence of liver microsomes from untreated, PB-treated, and PCB-treated rats. However, the ratio was approximately 1.5 using liver microsomes from MC-treated rats. The ratios between the sum of 1-BrPy trans-9,10-dihydrodiol and 1-BrPy 9,10-epoxide to Py trans-9,10-dihydrodiol, and to 1-BrPy trans-4,5-dihydrodiol were in the range of 0.1 to 0.5 using four rat liver microsomal preparations. These data revealed the effects of a bromo substituent at C1 of Py on the regioselectivity of various rat liver microsomal enzymes toward the oxidative metabolism at various positions of 1-BrPy. The enantiomeric compositions of K-region dihydrodiols formed by four rat liver microsomal preparations were determined by chiral stationary phase HPLC and circular dichroism spectral analyses; the percentage of R,R-enantiomers were: Py trans-4,5-dihydrodiol, 78-79%; 1-BrPy trans-4,5-dihydrodiol, 74-77%; 1-BrPy trans-9,10-dihydrodiol, 86-97%.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction / Q000187:drug effects; D004852:Epoxy Compounds / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011721:Pyrenes / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D001140:Aroclors; D004852:Epoxy Compounds; D011721:Pyrenes; D020111:Chlorodiphenyl (54% Chlorine); C056303:1-bromopyrene; D008748:Methylcholanthrene; D010634:Phenobarbital