**Author details**

144 Dehydrogenases

**13. Conclusion** 

cerebral infarction and ischemia [258].

suggesting 17β HSD10 as a potential target for the treatment of AD.Transgenic mice overexpressing human 17β-HSD10 suggesting that inhibition of 17β-HSD10 could protect from

17β-HSD type-12: The mammalian 17β-HSD12 was initially characterised as a 3-ketoacyl-CoA reductase, involved in the long-chain fatty acid synthesis, particularly essential for brain arachidonic acid synthesis. Both the human and the mouse 17β-HSD12 share 40% sequence similarity with 17β-HSD3, and the data indicate that 17β-HSD12 is an ancestor of 17β-HSD3. In human and rodents, 17β-HSD12 is expressed universally and the highest expression of 17β-HSD12 is detected in tissues involved in the lipid metabolism, including the liver, kidney hearth, and skeletal muscle. In mice, the expression has also been detected in brown and white adipose tissue. 17β-HSD12 expression is also regulated by sterol regulatory element binding proteins, identically to that shown to be involved in fatty acid and cholesterol biosynthesis. Interestingly, a reduced expression of 17β-HSD12 in cultured breast cancer cells results in significant inhibition of cell proliferation that is fully recovered by supplementation of arachidonic acid. In addition to its putative role in fatty acid synthesis, human 17β-HSD12 has been shown to catalyse the conversion of E1 to E2 in cultured cells, and the enzyme was suggested to be a major enzyme converting E1 to E2 in postmenopausal women [10]. Analysis of the HSD17B12-KO embryos indicated that the embryos initiated gastrulation but further organogenesis was severely disrupted. The mutant embryos exhibited severe defects in the neuronal development (ectoderm-derives), they failed to grow several mesoderm-derived structures. Therefore, the embryos at the age

of E8.5–E9.5 were avoid of all normal embryonic structures that caused their death.

HSD enzymes are broadly expressed in all steroidogenic organs as different isoforms with differential localization and function. HSD are key enzymes involved in growth and reproduction and they are considered as suitable targets to modulate the concentration of the potent steroids in case of steroid-dependent diseases. As they could act selectively in an intracrine manner, inhibitors of these enzymes might be superior to the existing endocrine therapies regarding the off-target effects. Although commont mechanisms operate in regulation of steroidogenesis, there are some differences/specificities between rodent and human, in particular the susceptibility of fetal testicular stereoidogenesis to environmental chemicals with estrogenic/antiandrogenic activity. As the latter appeared to be devoid of effect on fetal human testis, this should be taken into account when dial with risk assessment of endocrine disruptors for human reproductive health. Species specific diffences in steroiodogenesis cause real obstacles in investigation of HSD inhibitors. Some of the most active and selective inhibitors were investigated in vivo in animal disease-oriented models. They showed efficacy, but none of them reached the clinical trial stage. One reason for this might be the difficulty to identify an appropriate species to conduct the functional assays, as very potent inhibitors of the human enzyme show little activity toward HSD of other species (rodents). In this respect, experiments by using xenograft approach (human tissue xenografting in immunocompromised nude mice) would enable us to develop our Nina Atanassova *Inst. Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria* 

Yvetta Koeva *Dept. Anatomy and Histology, Medical University, Plovdiv, Bulgaria* 
