Continuous administration of organic nitrate decreases 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. Although our attention was mainly focused on the circulatory organs, most organic nitrates, including nitroglycerin (NTG), are metabolized in the liver, where nitric oxide (NO) is concomitantly produced from the organic nitrates. NO reacts with various molecules such as superoxide, heme, thiols, and oxygen. This paper examined whether hepatic P450 levels are also affected after organic nitrate administration, 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. We observed the level of hemeoxygenase-1 (HO-1) as the functional marker of hepatic P450, since one of the acute phase target proteins of NO induction is an inducible type of HO-1. Hepatic P450 was drastically decreased after 48 or 72 h of continuous NTG or ISDN infusion, when nitrate tolerance was observed, but it recovered 48 h after cessation of the NTG administration. HO-1 was induced within 24 h of continuous NTG infusion, but it returned to normal levels 48 h after cessation of NTG. The administration of sodium nitroprusside, an agent to which the animals showed no tolerance, did not induce HO-1 or P450 depletion. Chronic administration of organic nitrates significantly decreased hepatic P450. These results suggest that P450-dependent drug metabolism may be drastically affected after continuous organic nitrate administration.