**Author details**

P. Naik and S. Prasad *Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, TX, USA* 

L. Cucullo

*Vascular Drug Research Center, Texas Tech University Health Sciences Center, TX, USA Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, TX, USA* 

#### **9. References**

108 Dehydrogenases

**8. Conclusion** 

pathophysiologies.

**Author details** 

L. Cucullo

P. Naik and S. Prasad

The brain as well as the BBB have complex structural and functional physiology which demands a continuous supply of high energy. Bioenergetic pathways in the brain utilize multiple pathways (such as glycolytic metabolism, TCA cycle etc) to ensure that the energy requirements of the different cell types in the brain are fulfilled at all time. The BBB acts as a critical interface to buffer and influx energy substrates into the brain. Shuttling of multiple substrates such as glucose, lactose as well as glycogen derived lactate/glucose commonly occurs between the neurons and the astrocytes. Various DHOs are a critical part of these bioenergetic pathways and occurrence of DHO defect can lead to inborn errors in the metabolism followed by strong neurological complications. PDH is an imporant IEM which is directly linked to bioenergectic pathways such as TCA cycle and aerobic respiration. Apart from energy metabolism, BCKDH and SSD are IEMs that correlate to other pathways in the brain such as amino acid metabolism and neurotransmitter degradation. DHOs (such as ALDHs) also play an important role to further degrade the biogenic aldehydes derived from the degradation pathways of neurotransmitters such as for epinephrine, norepinephrine and GABA which are commonly synthesized in the brain. Furthermore, DHOs play an important role in oxidation of fatty acids as an energy supply. Although this does not occur in the brain, IEMs affecting these dehydrogenases have shown to correlate

with at least one reported neurological complication (such as Reye-like syndrome).

ALDH1A1, ALDH2, GDH2 and ABAD have been linked to PD.

Aging naturally promotes alterations and/or reduction in DHOs' activity which can alter mitochondrial functions leading to hypometabolism other metabolic dysfunction. This can ultimately facilitate the onset and progression of various neurological disorders such as Alzheimer's disease and PD. Specifically, altered expression/function of ABAD and ALDH2 have been associated with the pathogenesis of Alzheimer's disease whereas alteration of

In summary, DHOs play a critical role in supporting neuronal and BBB functions. They constitute an integral part of various metabolic pathways in the brain associated with energy metabolism, as well as synthesis and degradation of neurotransmitters. Their optimal functioning facilitates neuronal signaling and homeostasis. In born as well as acquired defects in DHOs have been shown to correlate with various CNS and BBB

*Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, TX, USA* 

*Vascular Drug Research Center, Texas Tech University Health Sciences Center, TX, USA Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, TX, USA* 


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**Chapter 6** 

© 2012 Atanassova and Koeva, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

**Hydrohysteroid Dehydrogenases –** 

allowing pre-receptor modulation of steroid hormone action [2].

Nina Atanassova and Yvetta Koeva

http://dx.doi.org/10.5772/54149

**1. Introduction** 

Additional information is available at the end of the chapter

**Biological Role and Clinical Importance – Review** 

Hydroxysteroid dehydrogenases (HSDs) belong to the NADPH/NAD+-dependent oxidoreductases, which interconvert ketones and the corresponding secondary alcohols. As their names imply, they catalyze the oxidoreduction in different positions of steroidal substrates (3α-, 3β-, 11β-, 17β-, 20α- and 20β-position). The steroid-converting HSDs play central roles in the biosynthesis and inactivation of steroid hormones, but some of them are also involved in the metabolism of diverse non-steroidal compounds [1]. The HSDs are integral parts of systemic (endocrine) and local (intracrine) mechanisms. In target tissues they convert inactive steroid hormones to their corresponding active forms and viceversa, thus modulating the transactivation of steroid hormone receptors or other elements of the non-genomic signal transduction pathways. Therefore, HSDs act as molecular switches

It is also well recognized that human and certain other primates are unique among animal species in having adrenals that secrete large amounts of inactive steroid precursors including dehydroepiandrosterone (DHEA). These steroids do not bind to the androgen receptor but exert either estrogenic or androgenic action after their conversion into active estrogens and/or androgens in target tissues [3]. Imbalanced action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in human. Hormone-dependent cancers are commonly lethal both in women and in men, with breast cancer being the most prevalent cancer in women and prostate cancer in men in several Western countries [4]. In addition, there are various other common hormonedependent diseases, such as polycystic ovary syndrome (PCOS) and endometriosis, having poorly understood aetiology and lacking efficient pharmacological treatment [5, 6]. However, changes in circulating hormone concentrations do not explain all pathophysiological processes occured in hormone-dependent tissues. A more inclusive explanation is provided by paracrine and intracrine action of sex steroids, namely the

