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Aging, acute oxidative injury and hepatocellular glucose transport in the rat

https://doi.org/10.1016/0928-4346(94)00186-9Get rights and content

Abstract

We studied the effects of aging and acute exposure to hydrogen peroxide on hepatocellular glucose transport to determine whether (1) acute oxidative stress impairs glucose transport, (2) aging is associated with reduced glucose transport and (3) there are similarities between these changes that may provide insight into the aging process. Glucose transport was measured in the perfused livers of young and aged rats using the multiple indicator-dilution method. There were significant reductions in the rate constants for glucose influx (P < 0.001) and a significant increase in the extracellular volume in the livers from aged rats (aged: 0.39 ± 0.05 ml/g, young: 0.27 ± 0.04 ml/g). However, the Km and Vmax for glucose influx in the livers from aged rats (44 ± 22 mM, 7.1 ± 1.4 μmol.s−1g−1, respectively) were not significantly different from the values in young rats (64 ± 20 mM, 8.8 ± 1.3 μmol.s−1g−1). In the livers of young rats, treatment with hydrogen peroxide caused a significant reduction in glucose transport from 1.18 ± 0.22 to 0.49 ± 0.25 μmol.s−1g−1. This was partly restored to 0.69 ± 0.20 μmol.s−1g−1 by occluding the outflow catheter and expanding the extracellular space. Thus, although aging did not influence the rate of glucose transport in the perfused rat liver, this may be due to a compensatory age-related increase in the extracellular volume. In conclusion, the changes observed in hepatocellular glucose transport in the aged liver could be simulated by oxidative injury in the young liver, suggesting a role for oxidative injury in the aging process.

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    Other changes that may affect the pharmacokinetics and/or pharmacodynamics of a chemical include aging-related reduction in the homeostatic reserve, efflux transporters, repair mechanisms, and apoptosis (Bales and Ritchie, 2002; Baum et al., 2007; Butler and Begg, 2008; Dodman, 2015; Elmadfa and Meyer, 2008; Hilmer, 2008; Houtkooper et al., 2011; Lichtman and Boparai, 2008; McLean and Le Couteur, 2004; Speakman et al., 2003; Toornvliet et al., 2006; Wolden-Hanson, 2010; Zhang et al., 2010). The volume of hepatocytes increases through maturity and subsequently becomes smaller, reducing the size of the liver in addition to an increasing the volume of dense body compartment and losing smooth endoplasmic reticulum (Le Couteur et al., 1995; Schmucker, 1990; Schmucker et al., 1978). The aging-related reduction in blood flow to the liver results in declined liver function and altered pharmacokinetic profiles of chemicals undergoing hepatic metabolism (Anantharaju et al., 2002; Frith et al., 2009; Hilmer, 2008; Hilmer et al., 2005; Ito et al., 2007; Kim et al., 2015; Le Couteur and McLean, 1998; Le Couteur et al., 2008; Marchesini et al., 1988; Mitchell et al., 2011b; Schmucker, 1998, 2001, 2005; Wynne et al., 1989a, 1989b; Zoli et al., 1999).

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