Effect of hypoxia and CO on a cytochrome P-450 mediated reaction in rabbit lungs

Evidence indicates that the difusion of O₂ and CO in tissue may be facilitated by a carrier molecule having a P₅₀ that approximates tissue O₂ partial pressure (P(O)₂; 1-15 Torr) and a much higher affinity for CO than for O₂. To determine whether cytochrome P-450 in lung satisfies these criteria, we measured the effect of hypoxia and of CO on the rate of metabolism of the cytochrome P-450 mediated O-demethylation of p-nitroanisole in isolated perfused rabbit lungs. Metabolism was inhibited by 50% of control at an estimated tissue P(O)₂ of 4 Torr (5.5 μM). When inspired CO₂ was kept at 200 Torr and inspired CO partial pressure (P(CO)) varied an estimated tissue P(CO)/P(O)₂ ratio of 0.025 reduced the reaction rate by 50% of control, but some metabolism persisted at P(CO)/P(O)₂ ratios larger than one. The relationship between reaction rate and p(CO)/P(O)₂ ratio could not be fit by a single value for Haldane constant for M (CO affinity/O₂ affinity) but could be described with a two-component model in which metabolism was equally divided between a high-affinity cytochrome (M = 200) and a low-affinity cytochrome (M = 2). These findings suggest that cytochrome P-450 could act as a carrier for O₂ and CO in tissue with low P(O)₂'s.