Continuous treatment with organic nitrate affects hepatic cytochrome P450

We previously reported that cytochrome P450 (P450) is a key enzyme of organic nitrate biotransformation and that P450 levels of the heart and its vessels markedly decreased at the development of nitrate tolerance. Escape from tolerance of organic nitrate by induction of cytochrome P450. Most organic nitrates, including nitroglycerin (NTG), are metabolized in the liver, where nitric oxide (NO) is concomitantly produced from the organic nitrates. Therefore, organic nitrate administration may also affect hepatic P450 levels, since the liver is the major organ of P450-related metabolism. Male Wistar rats were intravenously administrated NTG or isosorbide dinitrate (ISDN) for 24-96 h. Hepatic P450 was drastically decreased after 48 h or 72 h of continuous NTG or ISDN infusion, when nitrate tolerance was observed, but it recovered 48 h after cessation of the drug administration. hemeoxygenase-1 (HO-1) was induced within 24 h of continuous NTG infusion, but it returned to normal levels 48 h after cessation of the NTG. The administration of sodium nitroprusside, an agent to which the animals showed no tolerance, did not induce HO-1 or P450 depletion as judged by SDS-PAGE in combination with Western-blotting. These results suggest that P450-dependent drug metabolism may be drastically affected after continuous organic nitrate administration.