Products of gut-microbial tryptophan metabolism inhibit the steroid hormone-synthesizing cytochrome P450 11A1
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RESEARCH LETTER
Products of gut-microbial tryptophan metabolism inhibit the steroid hormone-synthesizing cytochrome P450 11A1 A. Mosa1 • A. Gerber1 • J. Neunzig1 • Rita Bernhardt1
Received: 26 November 2015 / Accepted: 17 January 2016 Ó Springer Science+Business Media New York 2016
Introduction Cytochromes P450 (P450s) are a superfamily of enzymes that catalyze the oxidative metabolism of a wide variety of xenobiotic chemical compounds, including drugs and carcinogens and play a key role in the synthesis of steroid hormones [1, 2]. The mitochondrial P450 11A1 (CYP11A1, EC 1.14.1.9), is a membrane-bound protein localized in the inner mitochondrial membrane of steroidogenic tissues such as the adrenal glands, gonads, and the gut [3], and commits the first and rate-limiting step of steroidogenesis, the side-chain cleavage of cholesterol to yield pregnenolone. First, cholesterol is hydroxlated at position C22 leading to the formation of 22(R)-hydroxycholesterol, which is then hydroxylated at position C20 to form 20(R), 22(R)-dihydroxy-cholesterol, followed by the oxidative cleavage of the bond between C20 and C22 resulting in pregnenolone [4]. The de novo production of steroid hormones such as the anti-inflammatory glucocorticoid cortisol in the gut is critical for maintenance of the intestinal homeostasis [5]. Disorders of intestinal steroidogenesis have been associated with inflammatory bowel diseases and are accompanied by lowered CYP11A1 expression [6], decreased glucocorticoid production [7], and cortisol-mediated expression of peroxisome proliferator-activated receptor gamma (PPARc) [8].
Indole and skatole are organic compounds formed as a product of tryptophan catabolism by gut bacteria, which serve as bacterial signaling molecules for a variety of biological actions [9]. In E. coli, indole is produced from tryptophan by the tryptophanase, which converts tryptophan into indole, pyruvate, and ammonia [10]. In human feces, indole concentrations have been reported to be between 0.25 and 1.1 mM [11]. The amount of indole in the gut greatly depends on exogenous tryptophan concentrations [12]. In this study, we describe an inhibitory effect of indole and skatole on CYP11A1, leading to a decrease in pregnenolone formation, the precursor of all mineralocorticoids, glucocorticoids, and sex steroids. Further, we demonstrate that both compounds serve as substrates for CYP11A1 and identify 5- and 6-hydroxyindole as novel products. Additionally, using cell culture experiments, we provide evidence that exogenous indole is able to interact with CYP11A1 localized at the inner mitochondrial membrane.
Methods Reagents Cholesterol, indole, skatole, hydroxyindole standards, and other chemicals used were obtained from Sigma-Aldrich. All the reagents and solvents were of analytical grade.
Mosa and Gerber contributed equally to this study. & Rita Bernhardt [email protected] 1
Institute of Biochemistry, Campus B 2.2, Saarland University, 66123 Saarbru¨cken, Germany
Protein expression and purification Heterologous expr
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