Oxidative injury reproduces age-related impairment of oxygen-dependent drug metabolism

The Oxygen Diffusion Barrier Hypothesis states that aging in the liver is a ssociated with restricted oxygen uptake that explains the age-related impai rment of phase I drug clearance observed in vivo with preservation of in vi tro phase I enzyme activity and in vivo phase II drug clearance. Aging in t he liver may be secondary to oxidative stress. Therefore we examined the ef fects of oxidative injury on oxygen uptake, and phase I and phase II drug m etabolism in the liver. Oxidative stress was induced in the perfused rat li ver with hydrogen peroxide. The intrinsic clearances of propranolol and mor phine were used as markers of phase I and phase II activity, respectively. Oxidative injury was associated with a 14 +/- 9% (P = 0.03) reduction in ox ygen uptake, The decrease in the intrinsic clearance of propranolol was gre ater than that of morphine (57 +/- 14% vs 34 +/- 7% P < 0.005). This result supports the concept of a restriction of oxygen supply constraining hepati c drug metabolism following oxidative stress. This has implications for agi ng and hepatic drug metabolism.