Share This Article:

Unbalanced biotransformation metabolism and oxidative stress status: implications for deficient fatty acid oxidation

Abstract Full-Text HTML Download Download as PDF (Size:233KB) PP. 43-48
DOI: 10.4236/health.2011.31009    4,417 Downloads   8,638 Views  


The concept of accumulating xenobiotics within the human body as a health risk is well known. However, these compounds can also be endo-genous, as in the case of inborn errors of me-tabolism, and lead to some of the same symp-toms as seen in xenobiotic intoxication. Bio-transformation of both exogenous and endo-genous toxic compounds is an important function of the liver, and the critical balance between these systems is of fundamental importance for cellular health. We propose a novel model, to describe the critical balance between Phase I and Phase II biotransformation and how a disturbance in this balance will increase the oxidative stress status, with resulting pathological consequences. We further used deficient fatty acid oxidation to verify the proposed model, as deficient fatty acid oxidation is associated with the accumulation of characteristic metabolites. These accumulating metabolites undergo both Phase I and Phase II biotransformation reactions, with resulting depletion of biotransformation substrates and co-factors. Depletion of these important biomolecules is capable of disturbing the balance between Phase I and Phase II reactions, and disturbance of this balance will increase oxidative stress status. The value of the proposed model is illustrated by its application to a clinical case investigated in our laboratory. In this case the possibility of deficient fatty acid oxidation only became evident once the critical balance between Phase I and Phase II biotransformation was restored with oral replenishment of biotransformation substrates. In addition to bio-chemical improvement, there was also significant clinical improvement. The significance of this model lies within the treatment possibilities, as the assessment of biotransformation metabolism and oxidative stress status can lead to the development of nutritional treatment strategies to correct imbalances. This in turn may reduce the chances of, or delay the onset of certain disease states.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Mels, C. , Westhuizen, F. , Pretorius, P. and Erasmus, E. (2011) Unbalanced biotransformation metabolism and oxidative stress status: implications for deficient fatty acid oxidation. Health, 3, 43-48. doi: 10.4236/health.2011.31009.


[1] Grant, D.M. (1991) Detoxification pathways in the liver. Journal of Inherited Metabolic Disease, 14, 421-430. doi:10.1007/BF01797915
[2] Liska, D.J. (1998) The detoxification enzyme systems. Alternative Medicine Review, 3, 187-198.
[3] Liska, D., Lyon, M. and Jones, D.S. (2006) Detoxification and biotransformation imbalances. Explore, 2, 122-140. doi:10.1208/aapsj0903031
[4] Lampe, J.W. (2007) Diet, genetic polymorphisms, detoxification, and health risks. Alternative Therapies in Health and Medicine, 13, S108-111.
[5] Newman, M. (2004) Urinary organic acid analysis: A powerful clinical tool. Townsend Letters for Doctors and Patients, 255, 80-90.
[6] Vangala, S. and Tonelli, A. (2007) Biomarkers, metabonomics, and drug development: Can inborn errors of metabolism help in understanding drug toxicity? The AAPS Journal, 9, E284-297. doi:10.1208/aapsj0903031
[7] Zhang, Q., Jingbo, P., Woods, C.G. and Andersen, M.E. (2009) Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses. Toxicology and Applied Pharmacology, 237, 345-356. doi:10.1016/j.taap.2009.04.005
[8] Turrens, J.F. (2003) Mitochondrial formation of reactive oxygen species. The Journal of Pysiology, 552, 335-344. doi:10.1113/jphysiol.2003.049478
[9] Cutler, R.G., Plummer, J., Chowdhury, K. and Heward, C. (2005) Oxidative stress profiling. Part II. Theory, technology, and practice. Annals of the New York Academy of Sciences, 1055, 136-158. doi:10.1196/annals.1323.031
[10] Townsend, D.M., Tew, K.D. and Tapiero, H. (2003) The importance of glutathione in human disease. Biomedicine & Pharmacotherapy, 57, 145-155. doi:10.1016/S0753-3322(03)00043-X
[11] Kidd, P.M. (1997) Glutathione: Systemic protectant against oxidative and free radical damage. Alternative Medicine Review, 2, 155-176.
[12] Pamplona, R. (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: A causal role in aging and longevity. Biochimica et Biophysica Acta, 1777, 1249-1262. doi:10.1016/j.bbabio.2008.07.003
[13] Catala, A. (2009) Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chemistry and Physics of Lipids, 157, 1-11. doi:10.1016/j.chemphyslip.2008.09.004
[14] Sim, K. G.; Hammond, J. and Wilcken, B. (2002) Strategies for the diagnosis of mitochondrial fatty acid β-oxidation disorders. Clinica Chimica Acta, 323, 37-58. doi:10.1016/S0009-8981(02)00182-1
[15] Vockley, J.; Whiteman, D. A. H. (2002) Defects of mitochondrial β-oxidation: A growing group of disorders. Neuromuscular Disorders, 12, 235-246. doi:10.1016/S0960-8966(01)00308-X
[16] Kompare, M. and Rizzo, W.B. (2008) Mitochondrial fatty-acid oxidation disorders. Seminars in Pediatric Neurology, 15, 140-149. doi:10.1016/j.spen.2008.05.008
[17] Fromenty, B. and Pessayre, D. (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacology & Therapeutics, 67, 101-154. doi:10.1016/0163-7258(95)00012-6
[18] Cooper, T. G.; Beevers, H. (1969) β-Oxidation in glyoxysomes from castor bean endosperm. Journal of Biological Chemistry, 244, 3514-3520.
[19] Inestrosa, N.C., Bronfman, M. and Leighton, F. (1979) Detection of peroxisomal fatty acyl-coenzyme A oxidase activity. Biochemical Journal, 182, 779-788.
[20] Foerster, E., Fahrenkemper, T., Rabe, U., Graf, P. and Sies, H. (1981) Peroxisomal fatty acid oxidation as detected by H2O2 production in intact perfused rat liver. Biochemical Journal, 196, 705-712.
[21] Johnson, E.F., Palmer, C.N.A., Griffin, K.J. and Hsu, M. (1996) Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation. The Journal of the Federation of American Societies for Experimental Biology, 10, 1241-1248.
[22] Hardwick, J.P. (2008) Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic disease. Biochemical Pharmacology, 75, 2263- 2275. doi:10.1016/j.bcp.2008.03.004
[23] Hayashi, S., Yasui, H. and Sakurai, H. (2005) Essential role of singlet oxygen species in cytochrome P450-dependant substrate oxygenation by rat liver microsomes. Drug Metabolism and Pharmacokinetics, 20, 14-23. doi:10.2133/dmpk.20.14
[24] Schuck, P.F.; Ferreira, G.C., Moura, A.P., Busanello, E.N. B., Tonin, A.M., Dutra-Filho, C.S. and Wajner, M. (2009) Medium-chain fatty acids accumulating in MCAD deficiency elicit lipid and protein oxidative damage and decrease non-enzymatic antioxidant defenses in rat brain. Neurochemistry International, 54, 519-525. doi:10.1016/j.neuint.2009.02.009
[25] Schuck, P.F., Ferreira, G.C., Tonin, A.M., Viegas, C.M., Busanello, E.N.B., Moura, A.P., Zanatta, A., Klamt, F. and Wajner, M. (2009) Evidence that the major metabolites accumulating in medium-chain acyl-CoA dehydrogenase deficiency disturb mitochondrial energy homeostasis in rat brain. Brain Research, 1296, 117-126. doi:10.1016/j.brainres.2009.08.053
[26] Mitchell, G.A., Gauthier, N., Lesimple, A., Wang, S.P., Mamer, O. and Qureshi, I. (2008) Hereditary and acquired diseases of acyl-coenzyme a metabolism. Molecular Genetics and Metabolism, 94, 4-15. doi:10.1016/j.ymgme.2007.12.005

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.