hrp0092fc3.3 | Multi-system Endocrine Disorders | ESPE2019

Variability in Drug Metabolizing Cytochrome P450 Activities Caused by Human Genetic Variations in NADPH Cytochrome P450 Oxidoreductase (POR)

Velazquez Maria Natalia Rojas , Parween Shaheena , Pandey Amit V

Background: A broad spectrum of human diseases, including abnormalities in steroidogenesis, are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR) (1-2). Cytochrome P450 proteins perform several reactions, including metabolism of steroids, drugs and other xenobiotics. Therefore, genetic variations in POR can impact many different metabolic pathways by changing the activities of cytochromes P450 (1). In 2004 the first human patients with defe...

hrp0092rfc13.6 | Adrenals and HP Axis | ESPE2019

Inhibitory Effects of Curcuminoids on the Enzymes from the Steroidogenic Pathway

Rodríguez Castaño Patricia , Pandey Amit V

Background: Turmeric is a popular ingredient in the cuisine of many Asian countries. It is also known for its use in Chinese and Ayurvedic medicine. It comes from the root of the Curcuma longa. Turmeric is rich in curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcumin has potent anti-inflammatory and anti-carcinogenic activities. Since many anti-cancer drugs target enzymes from the steroidogenic pathway, we tested the bioactivi...

hrp0092rfc15.3 | Late Breaking Abstracts | ESPE2019

Metformin Treatment Affects ACTH Receptor Activation and Downstream Signaling: A Potential Treatment for ACTH Excess Disorders and Management of Hyperandrogenic States

Parween Shaheena , Pandey Amit V. , Flueck Christa E.

Background: The peptide hormone adrenocorticotropin (ACTH or Corticotropin) is a major component of the stress response system in the Hypothalamus-Pituitary-Adrenal (HPA) axis. Under stress, it is secreted from the anterior pituitary and stimulates cortisol production from the adrenal cortex. Changes in ACTH production or action are associated with multiple disease conditions. In clinical situations like Cushing's disease, ectopic ACTH syndrome and congeni...

hrp0089fc1.3 | Adrenals & HPA Axis | ESPE2018

Targetting the Binding of ACTH to the Melanocortin Receptor by Structure Modeling and Design of Peptide antagonists to Block Excess Androgens in 21-hydroxylase Deficiency

Parween Shaheena , Fluck Christa E , Pandey Amit V

Background: The adrenocorticotropic hormone (ACTH) is a 39 amino acid polypeptide secreted by the anterior pituitary and regulates cortisol secretion from the adrenal cortex. Cortisol has negative feedback and regulates the synthesis and secretion of the ACTH. Excess ACTH is associated with a wide range of diseases including congenital adrenal hyperplasia (CAH). Classic CAH due to the 21-hydroxylase (CYP21A2) deficiency causes a reduction or loss of cortisol synthesis. Here th...

hrp0089fc7.4 | Fetal, Neonatal Endocrinology and Metabolism | ESPE2018

Altered Substrate Specificities and Metabolite Production by Aromatase (CYP19A1) Due to the R192H Mutation

Udhane Sameer S , Dick Bernhard , Pandey Amit V

Background: Aromatase (CYP19A1) a member of cytochrome P450 protein family is a major steroid metabolizing enzyme which converts androgens to estrogens. Mutations in aromatase can lead to autosomal recessive aromatase deficiency. An R192H mutation in CYP19A1 described earlier caused severe phenotype of aromatase deficiency with regressive virilization of the 46,XX new-born, but without signs of androgen excess during pregnancy. Computational studies suggested that R192H disrup...

hrp0089rfc1.2 | Adrenals & HPA Axis | ESPE2018

Changes in CYP19A1 and CYP3A4 Activities due to Population Genetic Variations in Human P450 Oxidoreductase

Parween Shaheena , Udhane Sameer S , Kagawa Norio , Pandey Amit V

Background: Cytochromes P450 proteins metabolize several steroid hormones, drugs and xenobiotics. All cytochromes P450s in the endoplasmic reticulum require P450 oxidoreductase (POR) for their catalytic activities. Earlier it has been shown that mutations in POR cause metabolic disorders of steroid hormone biosynthesis and also affect some drug metabolizing P450 activities. We aimed to characterize the mutations identified in nonclinical samples to access their effects on ster...

hrp0086p1-p362 | Gonads & DSD P1 | ESPE2016

Aromatase Activity is Disrupted by Mutations in P450 Oxidoreductase

Udhane Sameer S. , Parween Shaheena , Pandey Amit V.

Background: The steroidogenic enzyme aromatase (CYP19A1) is a protein located in endoplasmic reticulum (ER) that catalyzes the conversion of androgens to estrogens. Both deficiency and excess of aromatase activity lead to disease states implicating its role in human biology. Cytochrome P450 (CYP) enzymes in ER use reduced nicotinamide adenine dinucleotide phosphate through cytochrome P450 oxidoreductase (POR) for their metabolic activities. Mutations in POR cause disorders of ...

hrp0084fc10.4 | Perinatal Endocrinology | ESPE2015

Effect of P450 Oxidoreductase Variants on Metabolism by Cytochrome P450 Proteins

Parween Shaheena , Udhane Sameer S , Pandey Amit V

Background: A broad spectrum of human diseases including abnormalities in steroidogenesis is caused by mutations in the NADPH P450 oxidoreductase (POR). POR transfers electrons from NADPH to several small molecules, non-P450 redox partners and all microsomal cytochrome P450 proteins. POR disruption affects all partners with disastrous consequences and POR knock-out mice are embryonically lethal. A number of POR mutations and polymorphisms have been characterized from patients ...

hrp0089p1-p214 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology P1 | ESPE2018

In Silico and In vitro Studies of Human SRD5A2 Variants in Search for Activating Variants Explaining Androgen Excess Reveal Additional Loss of Function Variants

Katharopoulos Efstathios , Sauter Kay-Sara , Pandey Amit V , Fluck Christa E

Background: Androgens are steroid hormones necessary for human sex development. Testosterone (T) and the more potent dihydrotestosterone (DHT) are maybe the best known androgens, which exert their effect by binding and activating the androgen receptor. Steroid reductases 5α (SRD5As) catalyse the conversion of T to DHT in the classic androgen production pathway, or from 17-hydroxyprogesterone to 17OH-dihydroprogesterone, and androstenedione to androstanedione in alternate ...

hrp0084p2-313 | DSD | ESPE2015

A Novel Human CYP19A1 Deletion-Insertion Mutation Reveals that the C-terminus of the Aromatase Protein is Crucial for its Activity

Ladjouze Asmahane , Sauter Kay-Sarah , Ouarezki Yasmine , Kedji Leila , Laraba Abdenour , Pandey Amit V , Fluck Christa E

Background: The steroidogenic enzyme aromatase is encoded by the CYP19A1 gene. Aromatase activity is required for estrogen biosynthesis from androgen precursors in the ovary and several extragonadal tissues. The role of aromatase and thus estrogens for human biology is best illustrated by disease states, both deficiency and excess which might be caused by genetic disorders.Aim: A novel deletion-insertion mutation spanning from intron 10 to the 3...