Genetic enhancement of microsomal epoxide hydrolase improves metabolic detoxification but impairs cerebral blood flow regulation

Archives of Toxicology
A MarowskyM Arand

Abstract

Microsomal epoxide hydrolase (mEH) is a detoxifying enzyme for xenobiotic compounds. Enzymatic activity of mEH can be greatly increased by a point mutation, leading to an E404D amino acid exchange in its catalytic triad. Surprisingly, this variant is not found in any vertebrate species, despite the obvious advantage of accelerated detoxification. We hypothesized that this evolutionary avoidance is due to the fact that the mEH plays a dualistic role in detoxification and control of endogenous vascular signaling molecules. To test this, we generated mEH E404D mice and assessed them for detoxification capacity and vascular dynamics. In liver microsomes from these mice, turnover of the xenobiotic compound phenanthrene-9,10-oxide was four times faster compared to WT liver microsomes, confirming accelerated detoxification. mEH E404D animals also showed faster metabolization of a specific class of endogenous eicosanoids, arachidonic acid-derived epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). Significantly higher DHETs/EETs ratios were found in mEH E404D liver, urine, plasma, brain and cerebral endothelial cells compared to WT controls, suggesting a broad impact of the mEH mutant on endogenous EETs metabolis...Continue Reading

References

Nov 1, 1992·Journal of Applied Physiology·H M FrankelH R Weiss
Feb 1, 1992·Journal of Neurochemistry·S C AmrutheshE F Ellis
Jun 1, 1983·Archives of Biochemistry and Biophysics·N ChacosR W Estabrook
Mar 1, 1995·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·F FändrichF Oesch
May 1, 1996·Stroke; a Journal of Cerebral Circulation·N J AlkayedD R Harder
Jul 30, 1997·Biochemical and Biophysical Research Communications·R HollerA Meckey
Jul 17, 1999·British Journal of Cancer·D J HarrisonC A Smith
Mar 18, 2000·Toxicology Letters·C J OmiecinskiV Hosagrahara
Apr 3, 2001·Journal of Medical Genetics·P L ZusterzeelE A Steegers
Jun 20, 2001·Trends in Cardiovascular Medicine·M MedhoraD Harder
Oct 18, 2002·American Journal of Physiology. Heart and Circulatory Physiology·Xinqi PengRaymond C Koehler
Mar 26, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alison K BauerLeslie Recio
May 10, 2003·Circulation Research·Xueren WangChun Jiang
Nov 25, 2003·Prostaglandins & Other Lipid Mediators·David SacerdotiJohn C McGiff
Nov 5, 2005·Circulation Research·Scott EarleyJoseph E Brayden
Jan 11, 2007·The Journal of Obstetrics and Gynaecology Research·Ergun PinarbasiAli Cetin
Sep 13, 2008·American Journal of Physiology. Cell Physiology·Anke C WeblerIngrid Fleming
Oct 28, 2008·Journal of Lipid Research·Arthur A Spector
Feb 28, 2009·AJNR. American Journal of Neuroradiology·A S VagalM Zuccarello
Mar 24, 2009·American Journal of Physiology. Heart and Circulatory Physiology·Jeffrey J IliffNabil J Alkayed
May 26, 2009·Archives of Biochemistry and Biophysics·Shiling YangJorge H Capdevila
Dec 25, 2009·Biology Letters·Thomas Cavalier-Smith
Mar 13, 2010·Pflügers Archiv : European journal of physiology·William B Campbell, Ingrid Fleming
Nov 5, 2010·PloS One·Abdulwahab AhmedGuillermina Girardi
Apr 12, 2011·Molecular Carcinogenesis·Ellen L GoodeUNKNOWN Australian Ovarian Cancer Study Group
Jun 10, 2011·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Julie LeeBørge G Nordestgaard
Aug 23, 2011·Prostaglandins & Other Lipid Mediators·Karen WagnerBruce D Hammock
Jan 10, 2012·Disease Models & Mechanisms·Kathleen A PenningtonDanny J Schust
Jun 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Timo FrömelIngrid Fleming
Jun 8, 2013·Journal of Ovarian Research·Jian-Hong ZhongLe-Qun Li
Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Dipak PanigrahyMark W Kieran

❮ Previous
Next ❯

Citations

Oct 5, 2017·Archives of Toxicology·Anne MarowskyMichael Arand
Mar 3, 2020·Frontiers in Physiology·K Lockhart JamiesonJohn M Seubert
Dec 31, 2020·International Journal of Molecular Sciences·Jérémie Gautheron, Isabelle Jéru
Jul 24, 2021·Toxicological Research·Matthew L Edin, Darryl C Zeldin

❮ Previous
Next ❯

Methods Mentioned

BETA
amino
fluorescence imager

Related Concepts

Related Feeds

Basal Forebrain & Food Avoidance

Neurons in the basal forebrain play specific roles in regulating feeding. Here are the latest discoveries pertaining to the basal forebrain and food avoidance.