title: 6β-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice.
abstract: Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1(+/+) mice, 6β-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Ajeeth K
authors: AK
authors: Pingili
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Mehmet
authors: M
authors: Kara
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Nayaab S
authors: NS
authors: Khan
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Anne M
authors: AM
authors: Estes
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Zongtao
authors: Z
authors: Lin
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Wei
authors: W
authors: Li
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.).
authors: Frank J
authors: FJ
authors: Gonzalez
authors: From the Department of Pharmacology, College of Medicine (A.K.P., M.K., N.S.K., A.M.E., K.U.M.) and Department of Pharmaceutical Sciences, College of Pharmacy (Z.L., W.L.), University of Tennessee, Health Science Center, Memphis; and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD (F.J.G.). kmalik@uthsc.edu.
authors: Kafait U
authors: KU
authors: Malik
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D002369:Castration; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006915:Hydroxytestosterones / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values
chemical_list: D006915:Hydroxytestosterones; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C025591:6 beta-hydroxytestosterone; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1
keywords: CYP1B1 protein; castration; hypertension; oxidative stress