Effects of inhibition and induction of cytochrome P-450 isozymes on hyperoxic lung injury in rats.
Pulmonary oxygen toxicity most likely results from excessive production of reactive oxygen species. The role of the cytochromes P-450 in this process is controversial because these enzymes have been reported both to enhance hyperoxic lung injury and to protect from the damaging effects of 100% oxygen. We sought to further determine the role of the cytochromes P-450 in hyperoxic lung injury by inhibiting and inducing pulmonary cytochrome P-450 isozymes in rats. Treatment with the cytochrome P-450 inhibitor cimetidine or 8-methoxypsoralen did not improve survival or reduce lung edema in rats exposed to 100% oxygen. The activity of cytochrome P-450IIB1, the major pulmonary cytochrome P-450 isozyme in rats, was clearly inhibited by 8-methoxypsoralen. beta-Naphthoflavone (beta NF), a selective inducer of cytochrome P-450IA1, was administered in two-dose and five-dose regimens. The two-dose regimen produced significant and sustained induction of cytochrome P-450IA1 activity, but survival in these rats was not improved when exposed to 100% oxygen. In rats treated with five doses of beta NF, a small increase in survival time was found from 71.1 +/- 8.7 to 88.0 +/- 20.2 h; however, there was no difference in the induction of cytochrome P-450IA1 activity between this five-dose regimen and the two-dose regimen. The small improvement in survival after five doses of beta NF is thus unrelated to cytochrome P-450IA1 induction. We conclude that neither inhibition of cytochrome P-450IIB1 activity nor induction of cytochrome P-450IA1 activity protects adult rats against hyperoxic lung injury.
Todd
N W
NW
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Hunt
C M
CM
Kennedy
T P
TP
Piantadosi
C A
CA
Whorton
A R
AR
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D015153:Blotting, Western; D002927:Cimetidine / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004487:Edema / Q000139:chemically induced; D004790:Enzyme Induction; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D010100:Oxygen / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D019324:beta-Naphthoflavone; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D010100:Oxygen; D008730:Methoxsalen