Nitric oxide P450 inhibition

Minamiyama, Y., Takemura, S., Imaoka, S., Funae, Y., Tanimoto, Y., Inoue, M., Irreversible inhibition of cytochrome P450 by nitric oxide. J. Pharmacol. Exp. Then 283 (1997),... 

Nitric oxide formed from amyl nitrite inhibits cytochrome P450 (117) and ritonavir inhibits CYP2D6 (118), which has a major role in metamfetamine detoxification (119). This interaction could have led to fatal plasma concentrations of metamfetamine. It is therefore suggested that patients who take protease inhibitors are made aware of the potential risk of using any form of recreational drugs metabolized by CYP2D6, particularly metamfetamine. 

Nitric oxide inhibits cytochrome P450 metabolism of organic compounds, resulting in the presence of increased concentrations of organic compounds that may stimulate NMDA activity. 23 ... 

Wink, D.A., Osawa, Y., Darbysbite, J.F., Jones, C.R., Eshenaur, S.C., and Nims, R.W. (1993). Inhibition of cytochromes P450 by ntiric oxide and a nitric oxide releasing agent. Archs. Biochem. Biophys. 500 115-123. 

Ritonavir inhibits the cytochrome P450 isoenzyme CYP2D6, which is responsible for the demethylenation of ecstasy, so concurrent use leads to a sharp rise in ecstasy plasma levels. Poor liver function (due to alcoholism) may have been a contributory factor in one patient, and further CYP inhibition by nitric oxide (the metabolite of amyl nitrate) may have contributed to another case. An additional factor is that ecstasy may show non-linear pharmacokinetics. Metamfetamine is also metabolised by CYP2D6 and its levels would therefore similarly be raised by ritonavir. 

Wink DA, Osawa Y, Darbyshire JF, Jones CR, Eshen-aur SC, Nims RW (1993) Inhibition of cytochromes P450 by nitric oxide and a nitric oxide-releasing agent. Arch Biochem Biophys 300 115-123... 

Inducible nitric oxide synthase (iNOS) suppression by CO. iNOS is a cytochrome p450 type protein, and is responsible for the synthesis of nitric oxide (NO), which is known to cause an inflammatoiy response. Carbon monoxide has been shown to suppress the activity of this en me. It is clear that the CO binds to the haem in this protein and inhibits the two step reaction that occurs at the protein haem centre. CO can be considered as an anti inflammatoiy molecule as it can suppress the production of a molecule associated with pro-inflammatoiy action. This is useful and important when potentially using CO as a therapeutic molecule. 

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