Epoxide and Mechanism of Inhibition of Epoxide Hydrolases By Muhammad Hussaan Kamboh (M.phil Botany, Ph.D scholar) & ALI Akber (M.phil Botany, Ph.D scholar) & Sabeen Adil (Msc Botany)

What is Epoxide  Epoxides are organic three membered cyclic oxygen containing compound formed by the oxidation of olefins.  Epoxide also generated by enzymatic oxidation of xenobiotic compounds.  In human epoxide formed by the transformation of inhaled toxicants by cytochrome P-450 monooxygenase in human lungs.

Function Epoxide containing lipid response to stress as wound healing agent. Messengers in plant-pathogen interactions precursors of cutin Anti-cancer agents, and anti-HIV drugs are synthesized from epoxide-containing substrates

Why need inhibition of epoxide Epoxide have highly polarized oxygen-carbon bonds and strained ring, they are unstable in a water environment, and exhibit nucleophilic activity which cause toxic effects in reactions with cell components Such as, amino acids or purines. Reactive epoxides have been reported to have mutagenic, toxic and carcinogenic effects on DNA and proteins. So need for inhibition of E. M

Epoxide Hydrolases Epoxide hydrolases (EHs) are enzymes that hydrolyse epoxides to the corresponding diols. It open the ring of epoxide and produced less active diols.

Epoxide hydrolases EHs are found in nature and have been identified in many organisms including mammals, plants, insects and various microorganisms such as yeasts, fungi and bacteria. Function: Catabolism of specific carbon sources (in bacteria) Response to stress (in plants) Detoxification (mostly in mammals) Regulataion of signaling molecules (in mammals). It important in the synthesis of mycotoxins in yeast, fungi and bacteria.

Inhibitors of Epoxide Metals such as Hg2+, and Zn2+, Cd and Cu were the strongest inhibitor. While Nickel and Pb+2., Al 2+, Ba2+, Ca2+, Co2+, Fe2+, Fe2+, Mg2+, Mn2+, were considered moderate inhibitor. These ureas and amides are tight-binding competitive inhibitors. The more powerful inhibitors described herein were able to block sEH activity in vitro and in vivo in mice. Amide and Urea

Pharmacological inhibitor Pharmacological inhibitor such as chalcone oxides, methyl oleate, phenyl glycidiols, methyl epoxyoctadecenoate used for the treatment of pulmonary diseases, fever, inflammatory disease, and hypertension. dicyclohexylurea (DCU) 1-cyclohexyl-3-dodecylurea (CDU) 1-cyclohexyl-3- dodecanoylurea (CUDA) 1-adamantanyl-3-dodecanoylurea (AUDA)

Role in increasing concentration of (Epoxyeicostrienoic acid) EET inhibitors enhanced the EET concentration by inhibting the formation of DHET, EET produced from arachidonic acid by CYP epoxygenase, released from intracellular phospholipids, or taken up from an extracellular source accumulates intracellularly. As a result, higher concentrations of EET are available for a prolonged period to enhance autocrine or paracrine functional responses.

Function of EET Vascular relaxation by regulating Ca / K ion channel Act as Ant-inflammation agent Protect brain and myocardium against ischemic damage Increase the level of (cAMP) Increase level of adenlate cyclase Control blood pressure Control pain

Mechanism of Inhibition How control blood pressure, pain and inflammation? Epoxides of arachidonic acid (EETs) which are antihypertensive, anti-inflammatory and analgesic sEH inhibitors (sEHI) block Epoxide Hydrolases, as a result (Epoxyeicosatrienoic acids) EETs level are increased and then blood pressure, inflammation and pain are reduced

Advantage of Epoxide inhibition of in PLANTS Inhibiting the soluble epoxide hydrolase of plants can interfere with formation of plant cutin and thus can accelerate penetration of herbicides and other plant growth regulators. Epoxide hydrolase inhibitors also enhance herbicide action or to reduce herbicide resistance Formulations with the epoxide hydrolase inhibitor and herbicides can be prepared for foliage or root uptake.

Function … Inhibiting epoxide hydrolases should result in more endogenous JA in plants which act against insect. IN MAN EH inhibitors (sEHIs) have been developed to enhance the cardiovascular actions offered by EETs. IN RAT Injection of a sEHI to a spontaneously hypertensive rats (SHR) lowered blood pressure.