Steroid Sulphation and Drug Metabolism Research Group

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Group leader: Dr Vivek Dhir

Overview

My role within CEDAM is primarily Teaching focused and driving forward the link between our research strengths into the education that we deliver. My research interests are in the role of sulphation processes in steroid action and drug metabolism. Primary Translational targets collaborative projects in androgen excess syndromes and in colorectal cancer.

Our research group

Regulation of androgen synthesis and action

PAPS synthase type 2 (PAPSS2) as a regulator of DHEA sulphation and androgen action

  • DHEA is the principal precursor of androgen synthesis via the classic androgen synthesis pathway. Unconjugated DHEA can be converted directly to androgens, while the generation of DHEA sulphate (DHEAS) from DHEA represents an inactivation step. Our group has demonstrated inactivating mutations in the co-factor enzyme PAPS synthase 2 (PAPSS2) in a patient with androgen excess who presented with premature pubarche, subsequently progressing to early-onset PCOS. The identification of this important pre-receptor mechanism has highlighted the role of DHEA sulphation as a gate keeper for human androgen synthesis. Current research examines the role of the DHEA sulphation system in the pathogenesis of androgen excess disorders; in particular emphasis is placed on elucidating the molecular mechanisms of intra-cellular events controlling sulphation and steroid trafficking.

The role of PAPSS2 in Colecteral Cancer

  • The colon is a hotspot for sulphation processes, and in particular components of the sulphation pathway have been shown to be involved in the manifestation of tumours, the onset of metastasis and cancer. A key component of the sulphation pathway is  PAPSS2 has been previously implicated for the onset of metastasis in human carcinoma cell lines and the reduction of sulphated cell surface glycoprotein’s that are important in the prevention of malignant transformation of epithelial colon cancer cells.

Zebrafish as a model to study the biology of adrenal and liver sulphation

  • Sulphation processes are dependent on the bioavailability of PAPS generated by PAPS synthase of which there are two isoforms in humans; PAPSS1 and PAPSS2. The availability of PAPS is closely controlled by intra cellular trafficking processes and defects to these have been shown to be important in developmental processes and are apparent in some human colon cancers. Additionally, sulphation plays a key role in drug detoxification in the liver and androgen regulation in the adrenal glands.
  • To study the sulphation process in vivo our group is developing the zebrafish as a model. The zebrafish is an ideal because, similar to humans, it expresses two PAPSS isozymes and also has an adrenal gland equivalent, the interrenal organ. The development of the interrenal organ closely mimics mammalian adrenal development and hence zebrafish are viewed as a useful model for studying adrenal function .  We are assessing the distribution and functional significance of key molecules involved in sulphation, and we propose that these studies will provide insight into the differences between adrenal and liver sulphation and the implications of this for endocrine disease.

Current Projects

  • PAPS synthase type 2 (PAPSS2) as a regulator of DHEA sulphation and androgen action
  • The role of PAPSS2 in Colocteral Cancer
  • Zebrafish as a model to study the biology of adrenal and liver sulphation

Recent Publications

Reisch N, Högler W, Parajes S, Rose IT, Dhir V, Götzinger J, Arlt W and Krone N (2013) A diagnosis not to be missed: nonclassic steroid 11β-hydroxylase deficiency presenting with premature adrenarche and hirsutism. J Clin Endocrinol Metab 98(10):E1620-5

Reisch N, Idkowiak J, Hughes BA, Ivison HE, Abdul-Rahman OA, Hendon LG, Olney AH, Nielsen S, Harrison R, Blair EM, Dhir V, Krone N, Shackleton CH and Arlt W (2013) Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency. J Clin Endocrinol Metab 98(3):E528-36

Parajes S, Chan AO, But WM, Rose IT, Taylor AE, Dhir V, Arlt W and Krone N (2012) Delayed diagnosis of adrenal insufficiency in a patient with severe penoscrotal hypospadias due to two novel P450 side-change cleavage enzyme (CYP11A1) mutations (p.R360W; p.R405X). Eur J Endocrinol 167(6):881-5

Idkowiak J, Randell T, Dhir V, Patel P, Shackleton CH, Taylor NF, Krone N and Arlt W (2012) A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency. J Clin Endocrinol Metab 97(3):E465-75

Parajes S, Kamrath C, Rose IT, Taylor AE, Mooij CF, Dhir V, Grötzinger J, Arlt W and Krone N (2011) A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab 96(11):E1798-806

Parajes S, Loidi L, Reisch N, Dhir V, Rose IT, Hampel R, Quinkler M, Conway GS, Castro-Feijóo L, Araujo-Vilar D, Pombo M, Dominguez F, Williams EL, Cole TR, Kirk JM, Kaminsky E, Rumsby G, Arlt W and Krone N (2010) Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency. J Clin Endocrinol Metab 95(2):779-88

Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL and Arlt W (2009) Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 28;360(22):2310-8

Staff

Principal Investigator
Dr Vivek Dhir
- School of Clinical and Experimental Medicine

Internal Collaborators
Professor Wiebke Arlt
- School of Clinical and Experimental Medicine

Dr Nils Krone
- School of Clinical and Experimental Medicine

Dr Ferenc Mueller
- School of Clinical and Experimental Medicine

Dr Paul Foster
- School of Clinical and Experimental Medicine