INDUCTION OF PEROXISOMES BY TREATMENT WITH PERFLUOROOCTANOATE DOES NOT INCREASE RATES OF H2O2 PRODUCTION IN INTACT LIVER

被引:31
作者
HANDLER, JA [1 ]
SEED, CB [1 ]
BRADFORD, BU [1 ]
THURMAN, RG [1 ]
机构
[1] UNIV N CAROLINA,DEPT PHARMACOL,HEPATOBIOL & TOXICOL LAB,CB 7365,CHAPEL HILL,NC 27599
关键词
PEROXISOMES; H2O2; PRODUCTION; PERFLUOROOCTANOATE; LIVER;
D O I
10.1016/0378-4274(92)90047-N
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Increases in acyl coenzyme A (CoA) oxidase activity due to peroxisome proliferation are postulated to cause oxidative stress via elevated production of H2O2, leading to DNA damage. These changes are suspected to be responsible for tumor formation caused by non-genotoxic carcinogens which do not bind to DNA but cause proliferation of peroxisomes. However, the activity of the peroxisomal enzyme acyl CoA oxidase assayed in vitro in the presence of excess fatty acyl CoA substrate may not reflect rates of H2O2 generation in intact liver where fatty acid supply is carefully controlled in part by delivery of substrate. The purpose of this work was to determine if rates of hepatic H2O2 generation were altered in perfused liver and in vivo following induction of H2O2-generating acyl CoA oxidase activity. Injection of the potent peroxisome proliferating agent perfluorooctanoate into rats 5 days prior to sacrifice caused an expected 4-fold increase of H2O2-generating acyl CoA oxidase activity measured in hepatic homogenates. In contrast, rates of H2O2 generation in perfused liver measured spectrophotometrically (660-640 nm) through a lobe of the liver were not altered by perfluorooctanoate treatment (7.3 +/- 1.5 vs. 7.8 +/- 0.5-mu-mol/g/h in livers from untreated control rats). Similar treatment with perfluorooctanoate also increased in vitro acyl CoA oxidase activity 9-fold in livers from deermice; however, rates of elimination of methanol, a selective substrate for catalase in rodents whose oxidation is limited by the supply of H2O2, were not altered significantly in vivo (control, 110 +/- 11-mu-mol/g/h vs. perfluorooctanoate, 112 +/- 32-mu-mol/g/h). Taken together, these data demonstrate that elevation of H2O2 formation by acyl CoA oxidase activity measured in vitro is not necessarily associated with increases in rates of H2O2 generation in intact perfused liver or in vivo, most likely due to rate-limitation in intact cells by fatty acid supply. These data do not support the hypothesis that the induction of peroxisomes leads to excessive H2O2 production and oxidative stress. It follows that alternative hypotheses to explain carcinogenesis caused by peroxisome-proliferating agents need to be considered.
引用
收藏
页码:61 / 68
页数:8
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