title: Erectile Dysfunction Drugs Changed the Protein Expressions and Activities of Drug-Metabolising Enzymes in the Liver of Male Rats.
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.
authors: Biotechnology Department, Institute of Graduate Studies & Research, Alexandria University, 163 El Horreya Avenue 21526, P.O. Box 832, Alexandria, Egypt.
authors: Salah A
authors: 0000-0001-8113-4403
authors: SA
authors: Sheweita
authors: Biotechnology Department, Institute of Graduate Studies & Research, Alexandria University, 163 El Horreya Avenue 21526, P.O. Box 832, Alexandria, Egypt.
authors: Mona
authors: 0000-0003-2574-6565
authors: M
authors: Wally
authors: Department of Environmental Studies, Institute of Graduate Studies & Research, Alexandria University, Alexandria, Egypt.
authors: Mostafa
authors: M
authors: Hassan
mesh_terms: D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology* / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007172:Erectile Dysfunction / Q000188:drug therapy*; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D050216:Metabolic Detoxication, Phase I; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D018570:Risk Assessment; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000633:toxicity; D000068581:Tadalafil / Q000494:pharmacology* / Q000633:toxicity; D000069058:Vardenafil Dihydrochloride / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C000717351:Cyp2c23 protein, rat; D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D058986:Phosphodiesterase 5 Inhibitors; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D003577:Cytochrome P-450 Enzyme System; D000068677:Sildenafil Citrate; D000090762:Cytochrome P-450 CYP2J2