Abstract
Erectile dysfunction (ED) is a major health problem and is mainly associated with the persistent inability of men to maintain sufficient erection for satisfactory sexual performance. Millions of men are using sildenafil, vardenafil, and/or tadalafil for ED treatment. Cytochrome P450s (CYPs) play a central role in the metabolism of a wide range of xenobiotics as well as endogenous compounds. Susceptibility of individuals to the adverse effects of different drugs is mainly dependent on the expression of CYPs proteins. Therefore, changes in activities of phase I drug-metabolising enzymes [arylhydrocarbon hydroxylase (AHH), dimethylnitrosamine N-demethylase (DMN-dI), 7-ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase ((EROD)] and the protein expression of different CYPs isozymes (CYP1A2, CYP2E1, CYP2B1/2, CYP3A4, CYP2C23, and CYP2C6) were determined after treatment of male rats with either low or high doses of sildenafil (Viagra), tadalafil (Cialis), and/or vardenafil (Levitra) for 3 weeks. The present study showed that low doses of tadalafil and vardenafil increased DMN-dI activity by 32 and 23%, respectively. On the other hand, high doses of tadalafil, vardenafil, and sildenafil decreased such activity by 50, 56, and 52%, respectively. In addition, low doses of tadalafil and vardenafil induced the protein expression of CYP2E1. On the other hand, high doses of either tadalafil or sildenafil were more potent inhibitors to CYP2E1 expression than vardenafil. Moreover, low doses of both vardenafil and sildenafil markedly increased AHH activity by 162 and 247%, respectively, whereas high doses of tadalafil, vardenafil, and sildenafil inhibited such activity by 36, 49, and 57% and inhibited the EROD activity by 39, 49, and 33%, respectively. Low and high doses of tadalafil, vardenafil, and sildenafil inhibited the activity of NADPH-cytochrome c reductase as well as its protein expression. In addition, such drugs inhibited the expression of CYP B1/2 along with its corresponding enzyme marker ECOD activity. It is concluded that changes in the expression and activity of phase I drug-metabolising enzymes could change the normal metabolic pathways and might enhance the deleterious effects of exogenous as well as endogenous compounds.
Highlights
The male erectile dysfunction (ED) is a common and multifactorial disease, which strongly impairs the quality of man’s life
The present study showed that low doses of tadalafil and vardenafil caused significant (P < 0.001) increase in the DMNN-demethylase I (DMN-dI) activity by 32 and 23%, respectively (Table 2)
Low doses of tadalafil and vardenafil induced the protein expression of CYP2E1 (Figure 1). Such expression was inhibited after treatment of rats with the daily high dose of tadalafil, vardenafil, and sildenafil compared to control group (Figure 1)
Summary
The male erectile dysfunction (ED) is a common and multifactorial disease, which strongly impairs the quality of man’s life. According to the Massachusetts Male Aging Study, ED affects more than 150 million men worldwide and 50% of them are between the ages of 40 and 70 years [1]. Phosphodiesterase-5 inhibitors (PDE5Is) become the firstline therapy for millions of men suffering from ED. PDE5 inhibitors are structurally similar to those of the cGMP and competitively bind with PDE5 leading to inhibition of the cGMP hydrolysis. Accumulation of cGMP enhances the levels of nitric oxide (NO), which in turn activates guanylate cyclase to produce more cGMP, leading to smooth muscles relaxation of the corpus cavernous tissue and prolonged erection process [2]. The three EDDs (sildenafil (Viagra), tadalafil (Tadalafil), and vardenafil (Vardenafil) are well tolerated and effective, and the major clinical differences
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