title: Synthesis of atypical bile acids for use as investigative tools for the genetic defect of 3β-hydroxy-Δ(5)-C27-steroid oxidoreductase deficiency.
abstract: Deficiency of 3β-hydroxy-Δ(5)-C27-steroid oxidoreductase (HSD3B7), an enzyme catalyzing the second step in the pathway for bile acid synthesis, leads to a complete lack of the primary bile acids, cholic and chenodeoxycholic acids, and the accumulation of 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-Δ(5)-cholenoic acids. Patients affected by this autosomal recessive genetic defect develop cholestatic liver disease that is clinically responsive to primary bile acid therapy. Reference standards of these compounds are needed to facilitate diagnosis and to accurately quantify biochemical responses to therapy. Described are a novel synthesis of atypical bile acids that characterize the HSD3B7 deficiency and their effect on bile acid-activated nuclear receptors, target genes and cytochromes involved in bile acid homeostasis and detoxification. The failure of 3β-hydroxy-Δ(5)-cholenoic acids to function as FXR, PXR and CAR agonists and to exert hepatoprotective actions explains the mechanism for progressive cholestatic liver disease in patients with HSD3B7 deficiency.
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy. Electronic address: antimo.gioiello@unipg.it.
authors: Antimo
authors: A
authors: Gioiello
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy.
authors: Bruno
authors: B
authors: Cerra
authors: Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: Wujuan
authors: W
authors: Zhang
authors: Department of Farmacy, University of Parma, Viale delle Scienze 27/A, Parma I-43124, Italy.
authors: Gian Paolo
authors: GP
authors: Vallerini
authors: Department of Farmacy, University of Parma, Viale delle Scienze 27/A, Parma I-43124, Italy.
authors: Gabriele
authors: G
authors: Costantino
authors: TES Pharma, Via P. Togliatti, 20, Loc Taverne, I-06073 Corciano, Italy.
authors: Francesca
authors: F
authors: De Franco
authors: TES Pharma, Via P. Togliatti, 20, Loc Taverne, I-06073 Corciano, Italy.
authors: Daniela
authors: D
authors: Passeri
authors: Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy; TES Pharma, Via P. Togliatti, 20, Loc Taverne, I-06073 Corciano, Italy.
authors: Roberto
authors: R
authors: Pellicciari
authors: Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: Kenneth D R
authors: KD
authors: Setchell
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000138:chemical synthesis / Q000494:pharmacology*; D000090702:Constitutive Androstane Receptor; D056945:Hep G2 Cells; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated
keywords: 3β-Hydroxy-Δ5-C27-steroid oxidoreductase; Bile acids; Biomarkers; Diagnosis; Gene expression; Inborn errors; Mass spectrometry; Nuclear receptors; Synthesis