第32回大会シンポジウム1「環境物質に対する生体応答の分子機構」
紫外線によるグルタチオン転移酵素の誘導機構とその毒性学的意義
2004 年 26 巻 2 号 p. 107-115
詳細
2004 年 26 巻 2 号 p. 107-115
Levels of cholesterol 7α- and 7β-hydroperoxides (Ch 7-OOHs) in the skin of rats were investigated under different conditions in vivo such as aging or UVB-irradiation, and the results suggest that Ch 7-OOHs are good markers for lipid peroxidation. In the rat of any age, liver had no detectable level of Ch 7-OOHs. The Ch 7-OOHs were glutathione (GSH)-dependently reduced to the corresponding alcohols by GSH peroxidase (GSH Px) and only by the Alpha-class GSH S-transferases (GSTs) A1-1 and A1-3 among all isoforms of the GSTs occurring in the liver. On the other hand, rat skin had a very low level of GSH Px compared with the liver and lacked the subunit A1-bearing GSTs. Therefore, the absence or the presence of low levels of the enzyme systems which scavenge the cholesterol hydroperoxides in the skin of rats appears to be one of the main reasons for 1) the presence of Ch 7-OOHs in the skin of rats, 2) the increase in the levels of Ch 7-OOHs with age of rats or by UVB-irradiation to rats.
Enzyme, Western blot, and immunohistochemical analyses indicated that rat skin cytosol contained no detectable level of the Alpha-class GSTA4-4 which catalyzes the GSH conjugation of the toxic product, 4-hydroxy-2(E)-nonenal (HNE) , nonenzymatically formed from n-6 polyunsaturated fatty acid residues of lipids by lipid peroxidation. Rats irradiated with single doses (4,000-24,000 mJ/cm2) of UVB markedly expressed rGSTA4-4 in the skin at a level one-fifth that of the liver; at a single dose of 24,000 mJ/cm2, there was apparent specific activity toward HNE.
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase was irreversibly and (S)-selectively inactivated by the enantiomers of racemic HNE. Also, (S)-HNE was a much more potent agent than (R)-HNE for cell growth inhibition and induction of apoptosis. In rat liver cytosol, the HNE was detoxified 2.5- fold more (S)-selectively by GSH conjugation. The minor GST isoforms, A4-4, had a major role in the cytosolic (S)-selective GSH conjugation in the rat liver.
