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• W2156895077 abstract "Nitroglycerin (GTN) has been used to treat heart disease for many years. It is generally believed that GTN is a prodrug; however, the mechanism for GTN bioactivation remains unknown. Recent studies, using hepatic microsomes, have suggested the involvement of cytochrome P450 3A (CYP3A) in GTN biotransformation. Here, we used an animal model to test the hypothesis that aortic CYP3A plays a role in the bioactivation of GTN in vivo. Ketoconazole (KCZ), a potent CYP3A inhibitor, was given to rats (50 mg/kg i.p.) 1 hr before a bolus dose of GTN (2 mg/rat i.v.). KCZ decreased GTN-induced cGMP (cyclic guanosine monophosphate) levels by 20 to 30% (P < .05), without affecting basal or S-nitroso, N-acetyl penicillamine-induced levels of cGMP. When rats received dexamethasone (DEX, 30 mg/kg, 4 days i.p.), a strong CYP3A inducer, they exhibited a significant (approximately 50%) higher cGMP response to GTN than the control group. When rats received the combination treatment of both DEX and KCZ, they responded to GTN to the same extent as control rats. Although the effect of KCZ on aortic CYP3A activity cannot be detected (activity in control rats is below the detection limit), KCZ markedly inhibited CYP3A activity in rat livers (2.02 +/- 0.04 vs. 0.31 +/- 0.04 nmol/mg prot/min, P < .05, in control vs. KCZ-treated rats, respectively) and in DEX pretreated rat aorta (0.145 +/- 0.036 vs. 0.042 +/- 0.037 nmol/mg prot/min, P < .05, in rats treated with DEX alone vs. rats treated with both DEX and KCZ, respectively). KCZ did not elicit an effect on aortic glutathione S-transferases, another major metabolic enzyme responsible for GTN biotransformation. DEX enhanced the aortic GST mu activity by 3-fold. However, the activity of GST in aorta did not correlate with the cGMP response to GTN. In conclusion, our results demonstrate that CYP3A activity in aorta is correlated with GTN bioactivation in vivo, but the contribution of this enzyme to overall GTN bioactivation is limited." @default.
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• W2156895077 date "1997-06-01" @default.
• W2156895077 modified "2023-09-23" @default.
• W2156895077 title "Investigation of aortic CYP3A bioactivation of nitroglycerin in vivo." @default.
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