Energy restriction does not compensate for the reduced expression of hepatic drug-processing genes in mice with aging.

Liver is the major organ that eliminates xenobiotics from the body, a process that is accomplished by a series of drug-processing genes (DPGs). These genes encode transporters on both basolateral and apical membranes of hepatocytes, as well as phase I and II enzymes. The current study compares the expression of hepatic DPGs in adult and aged mouse livers and explores the potential effects of energy restriction (ER) on these genes during aging. Of 79 quantified hepatic DPGs, 52 were expressed lower in 24-month-old aged mice than in 12-month-old adult mice. Furthermore, the mRNA expression of multiple xenobiotic-activated transcription factors also decreased with age. Six-month ER exerted less of an effect on the hepatic DPGs than did aging. ER increased the mRNAs of two and decreased the mRNAs of nine DPGs in adult mice. In aged mice, ER increased the mRNAs of 10 and decreased the mRNAs of 5 DPGs. The only mRNA that was increased by both ER and aging was Gstm3. ER increased the mRNAs of Cyp2b10, Ugt1a9, Gsta1, and Oatp1a4 only in adult mice and decreased the mRNAs of Aldh6a1, Pon3, Ugt1a1, Sult1a1, and Atp8b1 only in aged mice. In summary, the reduced mRNA expression of hepatic DPGs in aged mice indicates decreased drug-processing capability, whereas ER did not compensate for the global reduction of hepatic DPG expression in aged mice. The hepatic transcription factors are likely to mediate the changes in hepatic DPG expression during aging and ER.