This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mulatero, P. Articles by Pascoe, L. Search for Related Content PubMed PubMed Citation Articles by Mulatero, P. Articles by Pascoe, L.

Recombinant CYP11B Genes Encode Enzymes that Can Catalyze Conversion of 11-Deoxycortisol to Cortisol, 18-Hydroxycortisol, and 18-Oxocortisol¹

INSERM U36 (P.M., K.M.C., X.J,. P.C., L.P.), Collège de France, 75005 Paris, France; Department of Medicine and Experimental Oncology (F.V., P.M.), University of Turin, Italy; Baker Medical Research Institute (K.M.C.), Prahran, 3181 Victoria, Australia; Service de Biochimie (B.A-F.), Hôpital de la Pitié-Salpétrière, 75651 Paris, France; and Harry S. Truman Memorial Hospital (C.G-S., M.F.), Department of Internal Medicine, Columbia Missouri 65201-5297

Address all correspondence and requests for reprints to: Leigh Pascoe, Fondation Jean Dausset CEPH, 27 rue Juliette Dodu, 75010 Paris, France. E-mail: leigh{at}cephb.fr

CYP11B1 (11ß-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11ß-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.

This article has been cited by other articles:

				P. Mulatero, C. Bertello, D. Rossato, G. Mengozzi, A. Milan, C. Garrone, G. Giraudo, G. Passarino, D. Garabello, A. Verhovez, et al. Roles of Clinical Criteria, Computed Tomography Scan, and Adrenal Vein Sampling in Differential Diagnosis of Primary Aldosteronism Subtypes J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1366 - 1371. [Abstract] [Full Text] [PDF]

				R. J. Auchus, D. W. Chandler, S. Singeetham, N. Chokshi, F. E. Nwariaku, B. L. Dolmatch, S. A. Holt, F. H. Wians Jr., S. C. Josephs, C. K. Trimmer, et al. Measurement of 18-Hydroxycorticosterone during Adrenal Vein Sampling for Primary Aldosteronism J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2648 - 2651. [Abstract] [Full Text] [PDF]

				P. Mulatero, A. Milan, F. Fallo, G. Regolisti, F. Pizzolo, C. Fardella, L. Mosso, L. Marafetti, F. Veglio, and M. Maccario Comparison of Confirmatory Tests for the Diagnosis of Primary Aldosteronism J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2618 - 2623. [Abstract] [Full Text] [PDF]

				H. Sanada, J. Yatabe, S. Midorikawa, S. Hashimoto, T. Watanabe, J. H. Moore, M. D. Ritchie, S. M. Williams, J. C. Pezzullo, M. Sasaki, et al. Single-Nucleotide Polymorphisms for Diagnosis of Salt-Sensitive Hypertension Clin. Chem., March 1, 2006; 52(3): 352 - 360. [Abstract] [Full Text] [PDF]

				E. M. Freel, L. A. Shakerdi, E. C. Friel, A. M. Wallace, E. Davies, R. Fraser, and J. M. C. Connell Studies on the Origin of Circulating 18-Hydroxycortisol and 18-Oxocortisol in Normal Human Subjects J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4628 - 4633. [Abstract] [Full Text] [PDF]

				P. Mulatero, M. Stowasser, K.-C. Loh, C. E. Fardella, R. D. Gordon, L. Mosso, C. E. Gomez-Sanchez, F. Veglio, and W. F. Young Jr. Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1045 - 1050. [Abstract] [Full Text] [PDF]

				P. Mulatero, F. Rabbia, A. Milan, C. Paglieri, F. Morello, L. Chiandussi, and F. Veglio Drug Effects on Aldosterone/Plasma Renin Activity Ratio in Primary Aldosteronism Hypertension, December 1, 2002; 40(6): 897 - 902. [Abstract] [Full Text] [PDF]

				P. Mulatero, S. M. di Cella, T. A. Williams, A. Milan, G. Mengozzi, L. Chiandussi, C. E. Gomez-Sanchez, and F. Veglio Glucocorticoid Remediable Aldosteronism: Low Morbidity and Mortality in a Four-Generation Italian Pedigree J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3187 - 3191. [Abstract] [Full Text] [PDF]

				P. Mulatero, T. A. Williams, A. Milan, C. Paglieri, F. Rabbia, F. Fallo, and F. Veglio Blood Pressure in Patients with Primary Aldosteronism Is Influenced by Bradykinin B2 Receptor and {alpha}-Adducin Gene Polymorphisms J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3337 - 3343. [Abstract] [Full Text] [PDF]

				C. E. Fardella, M. Pinto, L. Mosso, C. Gomez-Sanchez, J. Jalil, and J. Montero Genetic Study of Patients with Dexamethasone-Suppressible Aldosteronism without the Chimeric CYP11B1/CYP11B2 Gene J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4805 - 4807. [Abstract] [Full Text] [PDF]

				S. Portrat, P. Mulatero, K. M. Curnow, J.-L. Chaussain, Y. Morel, and L. Pascoe Deletion Hybrid Genes, due to Unequal Crossing Over between CYP11B1 (11{beta}-Hydroxylase) and CYP11B2(Aldosterone Synthase) Cause Steroid 11{beta}-Hydroxylase Deficiency and Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3197 - 3201. [Abstract] [Full Text] [PDF]

				P. Mulatero, F. Rabbia, and F. Veglio Paraneoplastic Hyperaldosteronism Associated with Non-Hodgkin's Lymphoma N. Engl. J. Med., May 17, 2001; 344(20): 1558 - 1559. [Full Text] [PDF]

				Glucocorticoid-Remediable Aldosteronism J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4341 - 4344. [Full Text]

				C. Pilon, P. Mulatero, L. Barzon, F. Veglio, C. Garrone, M. Boscaro, N. Sonino, and F. Fallo Mutations in CYP11B1 Gene Converting 11{beta}-Hydroxylase into an Aldosterone-Producing Enzyme Are Not Present in Aldosterone-Producing Adenomas J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 4228 - 4231. [Abstract] [Full Text]

				B. I. Cerame, R. S. Newfield, L. Pascoe, K. M. Curnow, S. Nimkarn, T. F. Roe, M. I. New, and R. C. Wilson Prenatal Diagnosis and Treatment of 11{beta}-Hydroxylase Deficiency Congenital Adrenal Hyperplasia Resulting in Normal Female Genitalia J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3129 - 3134. [Abstract] [Full Text]