Nitric oxide (NO) mediates a variety of important biological functions including neurotransmission, platelet aggregation, penile erection, and vasodilation. It is thought that many of the physiological actions of NO are due to the activation of heme-dependent guanylate cyclase. We have found that NO may have other cellular targets, including other hemoproteins. Last year we observed that exogenously applied nitric oxide could inhibit cytochrome P-450 in vitro with the use of a microsomal system. We have now shown that endogenously formed NO can inhibit the activity of P-450 cytochromes in primary cultures of hepatocytes. Not all cytochrome P-450 dependent activities were inhibited to the same extent, indicating that the inhibition was selective. These findings suggest that the hepatic metabolism of drugs may be altered in patients with septic shock, where NO synthesis is known to be highly induced. In addition, we have shown with the use of intact human platelets that endogenously produced NO inhibits platelet lipoxygenase and prostaglandin H synthase. Thus, it appears that we have identified some new targets for the biological effects of NO. A flavohemoprotein, nitric oxide synthase is responsible for formation of NO from arginine. It was discovered that phencyclidine, a psychotomimetic agent and drug of abuse, can irreversible inactivate nitric oxide synthase. Owing to the multitude of physiological effects of NO, the inactivation of the enzyme responsible for nitric oxide synthesis by xenobiotics may have important pharmacological and toxicological effects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Intramural Research (Z01)
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National Heart, Lung, and Blood Institute
United States
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