We propose to study effects of chronic hypoxemia and chronic hemoglobinemia on hepatic heme, cytochrome P450 and drug metabolism. Cytochrome P450 is the terminal enzyme in the mixed-function oxidase system which is responsible for metabilism/activation of numerous endogenous substrates and exogenous drugs, toxins and carcinogens. In addition to its central role in drug metabolism, liver cytochrome P450 also plays a central role in hepatic heme metabolism since about 2/3 of the heme synthesized in the liver is uitlized in P450. We have found that rats chronically exposed to hypoxia (PO2 less than 78 torr) develop polycythemia and plasma hemoglobinemia. The hemoglobinemia is not due to intravascular hemolysis since erythrocyte survival is normal. The chronically hypoxemic rats have increased levels of hepatic heme oxygenase (the rate-limiting enzyme of heme breakdown). Despite this increase, basal levels of liver cytochrome P450 and inducibility of P450 after phenobarbital administration were also increased in chronically hypoxemic rats. The increases in P450 were accompanied by increased rates of drug metabolism in vivo. Despite the increases in levels of P450, the hypoxemic rats had decreased levels and decreased inducibility of liver 5-aminolevulinate synthetase, the rate-limiting enzyme of hepatic heme synthesis. We now propose to characterize in detail the hepatic metabolism of heme, P450 and drugs in chronically hypoxemic rats. In a pilot study we also propose to explore the possible effects of concomitant chronic hypercapnic exposure on these parameters. The significance of these studies is three-fold: (1) They will advance knowledge of the pathophysiology of chronic hypoxia; (2) They will advance understanding of factors controlling heme, cytochrome P450 and drug metabolism; (3) They will provide clinically relevant information concerning the metabolic effects of soluble heme preparations such as free hemoglobin, hematin or methemalbumin. This information is important since these preparations are being used in the therapy of acute porphyria and, in addition, have been proposed for treatment of other disorders.

R01HL036438

1985-09-01

1986-11-30