Enhanced potential for oxidative stress in livers of senescent rats by the peroxisome proliferator-activated receptor alpha agonist perfluorooctanoic acid.
Aging sensitizes the liver to the hepatocarcinogenic effect of PPARalpha agonists via unknown mechanisms. This study was designed to investigate age-dependent, hepatic effects of the non-metabolizable PPARalpha agonist perfluorooctanoic acid (PFOA) on the delicate balance between activities of pathways involved in H(2)O(2) production and elimination. Male Fischer-344 rats, ranging in age from juvenile (4 weeks old), post puberty (10 weeks old), mature adulthood (20 weeks old), middle age (50 weeks old), to senescence (100 weeks old), were treated intragastrically with either 150mg PFOA/kg in 0.5ml corn oil, or with corn oil alone. Animals were sacrificed at predetermined time-points ranging from 0-28 days post PFOA or oil administration. Hepatic peroxisomal beta-oxidizing activities were significantly elevated (four- to six-fold) in all age groups by PFOA. While levels declined to near basal values within 3-7 days in 4 and 10, they remained elevated for an additional week in 20-, 50- and 100-week-old rats. However, catalase activity was significantly lower in senescent livers compared with all other groups. In conclusion, aging does not appear to hinder the capacity of the liver to produce excess H(2)O(2) through peroxisomal beta-oxidation upon exposure to PPAR agonists. However, the reduced ability of the senescent liver to recover from PFOA-induced potential increase in H(2)O(2) production, coupled with the apparent diminished capacity of this liver to decompose H(2)O(2), enhances the potential for hepatic oxidative damage in aged animals. This may explain the enhanced susceptibility of the senescent liver to the hepatocarcinogenic effect of PPAR agonists.
Badr
Mostafa Z
MZ
University of Missouri-Kansas City, 64108, USA. badrm@umkc.edu
Birnbaum
Linda S
LS
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002210:Caprylates / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D005466:Fluorocarbons / Q000494:pharmacology*; D006529:Hepatomegaly / Q000139:chemically induced; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*
D002210:Caprylates; D005466:Fluorocarbons; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C023036:perfluorooctanoic acid; D006861:Hydrogen Peroxide; D002374:Catalase