ASSOCIATIONS BETWEEN CHEMICAL PROPERTIES AND OXIDATIVE DAMAGE DUE TO NITROPHENANTHRENES AND THEIR RELATED COMPOUNDS IN PRIMARY RAT HEPATOCYTES

Abstract

Nitrated derivatives of phenanthrene, azaphenanthrene, and their N-oxides were synthesized, and their chemical properties, LUMO energy, the first and second reduction potentials, and dihedral angle of nitro groups were investigated. On orientation of 22 nitrophenanthrenes (NPhs), and 19 nitroazaphenanthrenes (NAPhs) containing their N-oxides (NPhOs), NPhs and NAPhs substituted at positions 2, 3, 6, and 7 were almost coplanar to the aromatic ring, while those at positions 1, 5, 8, 9, and 10 were almost perpendicular. On the other hand, primary rat hepatocytes prepared from SD rats efficiently induced 8-oxodeoxyguanine (8-oxo-Gua) of 4-nitroquinoline N-oxide (4-NQO), a mutagen and carcinogen. 8-oxo-Gua formed due to oxidative damage was dose dependent at levels from 1.0 to 5.0 nM of 4-NQO. 8-oxo-Gua formation of NPhs and NAPhs in primary rat hepatocytes was determined, and the results significantly correlated with the first reduction potentials (r = 0.906) and LUMO energy (r = 0.874) of these derivatives. It was concluded that the nitro group of Phs and APhs were metabolized by the NADPH-cytochrome p450 enzyme in primary rat hepatocytes, and a radical anion of NPhs was induced. Finally, the hydroxyl radicals induced promoted hydroxylation at the 8 position of the guanine residue. It was found that these metabolic pathways were closely associated with the first reduction potentials, and the LUMO energy of NPhs and NAPhs, as well as 8-oxo-Gua formation were related to these chemical properties.

Keywords:

• nitroazaphenanthrenes
• nitrophenanthrenes
• 8-oxodeoxyguanosine

Notes

*8-NO2, 33.5; 1-NO2, 24.7.

^a LUMO energy and dihedral angle were obtained by AM1 calculations based on the structure that was optimized by PM3.

^b LUMO energy and dihedral angle were obtained by AM1 calculations based on the structure that was optimized by PM3.