Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Abstract only
Publication Acceptance Date: 12/10/2000
Publication Date: 3/7/2001
Citation: Johnson, W.T. 2001. Mitochondrial oxidative stress may contribute to the induction of hepatic heme oxygenase-1 in copper deficient rats [astract]. The Federation of American Societies for Experimental Biology Journal. 15:A271. Interpretive Summary:
Technical Abstract: Although copper (Cu) deficiency increases heme oxygenase (HO) activity in rat liver, the mechanism for the increase is not clear. The catalytic activity of HO exhibits an absolute requirement for NADPH cytochrome P450 reductase (P450R) and thus, the increase in HO activity may result from either a direct effect on HO or from an indirect effect on P450R. Accordingly, the contents of HO-1 and P450R in hepatic microsomes isolated from rats fed either Cu-deficient diet (0.3 mg Cu/kg) or Cu-adequate diet (6 mgCu/kg) were determined by immunoblotting. Optical density units obtained from scanning densitometry (mean+/-SEM) were 4.59+/-0.17 and 2.66+/-0.34 for HO-1 (P<0.05, one-tail t-test) and 1.11+/-0.08 and 0.99+/- 0.15 for P450R (P>0.05) in copper-deficient (N=10) and control rats (N=9), respectively. This finding indicates that Cu deficiency increases HO-1 but has no effect on P450R and that induction of HO-1 is a likely explanation for increased hepatic HO activity caused by Cu deficiency. A mechanism for HO-1 induction during Cu deficiency may involve increased mitochondrial oxidative stress resulting from decreased cytochrome c oxidase and respiratory complex I activities. In the present study, rates of hydrogen peroxide production (mean+/-SEM) by isolated hepatic mitochondria in the presence of 10mM glutamate were 1.25+/-0.18 and 0.84+/-0.11 pmol/(sec x mg protein) (P<0.05) for Cu-deficient and control rats, respectively. HO-1 is induced by hydrogen peroxide and thus, the increase in HO-1 during Cu deficiency may be at least a partial consequence of increased cellular concentrations of hydrogen peroxide resulting from impaired mitochondrial electron transport.