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Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Another study has applied a GWAS approach to explore the relationships between genetic polymorphisms and CYP expression or enzyme activities with 466 human liver samples (X. Yang et al. 2010). This interesting study has revealed sets of SNPs associated with CYP traits and suggested the existence of both cis-regulation of CYP expression (especially for CYP2D6) and more complex trans-regulation of CYP activity. CYP3A5, 2D6, 4F12, and 2E1 each have more than 30 cis-SNPs. CYP2D6 is regulated by 1665 genes and CYP2C19 is related to 3360 genes. In addition to the SNPs rs8138080, rs5751247, and rs17478227, several novel SNPs associated with CYP2D6 expression and enzyme activity are identified and validated in an independent human cohort. Of the 54 SNPs associated with CYP enzyme activities, 30 are associated with CYP2D6 activity, and they are all located within 200-kb distance of the physical location of the CYP2D6 gene, demonstrating mainly cis genetic regulation of CYP2D6 enzyme activity. By constructing a weighted coexpression network and a Bayesian regulatory network, the authors have defined the human liver transcriptional network structure, uncovered subnetworks representative of the CYP regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1 (X. Yang et al. 2010). EHHADH and ACSM3 are upstream of the pathways and their regulation is mediated through CYP2CJ9, while the downstream CYP targets include CYP2C9, 3A7, 3A4, and 3A43. Another two putative CYP regulators, SLC10A1 and AKR1D1, generate a separate branch and are upstream of eight CYP genes and seven known CYP regulators: PGRMC1, CEBPD, FOXA2, NR1I3/CAR, NR1I2/PXR, PPARG, and HNF4A. The authors have identified SLC10A1, AKR1D1, GLYAT, ETNK2, LIME1, ZGPAT, BTD, ETNK2, KLKB1, FMO3, LIMK2, EHHADH, and ACSM3 to be the top global regulators, each with more than 40 downstream nodes (X. Yang et al. 2010). Therefore, SLC10A1, AKR1D1, EHHADH, and ACSM3 are identified as both global regulators and P450 regulators. The CYP subnetworks are then validated using gene signatures responsive to ligands of known CYP regulators in mouse and rat. These data demonstrate networked regulating mechanisms of human CYPs in a coordinated manner in the liver. Further functional and validation studies are needed to verify these findings.
A review of berotralstat for the treatment of hereditary angioedema
Published in Expert Review of Clinical Immunology, 2023
Henriette Farkas, Zsuzsanna Balla
Other drugs act by inhibiting prekallikrein, ultimately reducing bradykinin release. Donidalorsen (IONIS-PKK-LRx®) can selectively reduce mRNA synthesis of hepatic plasma prekallikrein, with phase 3 trials started in December 2021. NTLA-2002® targets the inactivation of the Kallikrein B1 (KLKB1) gene and is in Phase I and II of clinical development. Phase II studies with the oral PKa inhibitor KVD824® started in September 2021. Drug developments will significantly increase the number of drugs that can be administered as long-term prophylaxis, improving and broadening the spectrum of personalized treatment. It is important to make the administration of these drugs as convenient and simple as possible, and the future challenge is to make advanced, targeted treatments available to as many patients with hereditary angioedema as possible.
The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Dorsa Sohaei, Morley Hollenberg, Sok-Ja Janket, Eleftherios P. Diamandis, Gennady Poda, Ioannis Prassas
Another level amendable to intervention in the KKS is that of KLK1 and KLKB1, which are located upstream of the bradykinin receptors. By reducing the activity of these kallikreins, this in turn reduces the production of kinins and bradykinin receptor activation. KLK1 inhibitors are in development from Ferring (CH-2856; FE-999024; VA-999024, preclinical, pancreatitis and allergic asthma), GlaxoSmithKline (Clarivate #1036177, biological testing, Netherton syndrome), and KalVista Pharmaceuticals (Clarivate #799797, biological testing, vascular retinopathy). As highlighted, drugs that target KLK1 are at the research and preclinical stage, therefore KLKB1 would likely be quicker to reposition. KLKB1 inhibitors are in development from Bristol-Myers Squibb (Milvexian, Phase III, deep vein thrombosis) and BioCryst: Avoralstat and Berotralstat hydrochloride (Phase II, hereditary angioedema). In vitro and vitro modeling of avoralstat shows potential for it to be repurposed for COVID-19 infection [93]. Specifically, avoralstat demonstrated inhibition of transmembrane serine protease 2 (TMPRSS2), a protease required for SARS-CoV-2 viral entry. It demonstrated inhibition of viral entry in human airway epithelial cells as well as reduced viral infection based on lung viral titer and reduced weight loss in mice when administered prophylactically.
Genetic aspects of idiopathic asthenozoospermia as a cause of male infertility
Published in Human Fertility, 2020
Zohreh Heidary, Kioomars Saliminejad, Majid Zaki-Dizaji, Hamid Reza Khorram Khorshid
Hyperviscosity, or the persistence over time of a homogeneous semen stickiness and adherence, is a less explored infertility-related phenotype that has been thought to negatively impact spermatozoa motility, count and progression in the female reproductive tract, often impairing fertilization (Du Plessis, Gokul, & Agarwal, 2013). Several proteins are known to play key roles in the cascade of semen coagulation and liquefaction including the kallikrein (KLK) family, that was found on chromosome 19q13.3–13.4, and the whey-acidic-protein four-disulfide core domain (WFDC) cluster, located at chromosome 20q13 (Clauss, Lilja, & Lundwall, 2002). Human Kallikreins are a subgroup of serine proteases which are divided into the tissue and plasma kallikreins. The tissue Kallikrein loci encode a family of fifteen closely related serine proteases with pervasive activities in diverse proteolytic cascades; while the plasma kallikrein has no known paralogue and encode only one serine protease (KLKB1). Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation (Michael et al., 2006; Pathak, Wong, Dreveny, & Emsley, 2013).