Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism
PHARMACOGENOMICS JOURNAL
Authors: Modeste Alexandre Yahouedehou, Setondji Cocou; Adorno, Elisangela Vitoria; da Guarda, Caroline Conceicao; Ndidi, Uche Samuel; Carvalho, Suellen Pinheiro; Santiago, Rayra Pereira; Aleluia, Milena Magalhaes; de Oliveira, Rodrigo Mota; Goncalves, Marilda de Souza
Abstract
Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.
Potent and Selective Inhibitors of Long Chain L-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats
ACS MEDICINAL CHEMISTRY LETTERS
Authors: Barawkar, Dinesh A.; Meru, Ashwin; Bandyopadhyay, Anish; Banerjee, Abir; Deshpande, Anil M.; Athare, Chandrashekhar; Koduru, Chandrasekhar; Khose, Goraksha; Gundu, Jayasagar; Mahajan, Koshu; Patil, Pradeep; Kandalkar, Sachin R.; Niranjan, Sanjay; Bhosale, Shubhangi; De, Siddhartha; Mulchopadhyay, Sudit; Chaudhary, Sumit; Koul, Summon; Singh, Umesh; Chugh, Anita; Palle, Venkata P.; Mookhtiar, Kasim A.; Vacca, Joseph; Chakravarty, Prasun K.; Nargund, Ravi P.; Wright, Samuel D.; Roy, Sophie; Graziano, Michael P.; Singh, Sheo B.; Cully, Doris; Cai, Tian-Quan
Abstract
L-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.
COA
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