Abstract
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.
Highlights
The indispensable role of the liver in the biotransformation or detoxification of a variety of exogenous and endogenous compounds is accomplished by two groups of enzymatic modifications known as Phase I and Phase II biotransformation metabolism
Explaining the development of the phenotypic characteristics of metabolic diseases is a formidable challenge. To this end we propose a model to help explain the pathological outcomes of induced and inborn errors of metabolism
This model entails that unbalanced biotransformation metabolism due to depletion of Phase II substrates and co-factors can be the first linkage in a chain of events with severe pathological outcomes. It is vital for scientific advancement and clinical applications that the phenomenon of unbalanced biotransformation metabolism be considered as a primary cause of metabolic aberrations manifesting as increased oxidative stress status
Summary
The indispensable role of the liver in the biotransformation or detoxification of a variety of exogenous and endogenous compounds is accomplished by two groups of enzymatic modifications known as Phase I and Phase II biotransformation metabolism. Explaining the development of the phenotypic characteristics of metabolic diseases is a formidable challenge To this end we propose a model to help explain the pathological outcomes of induced and inborn errors of metabolism. This model entails that unbalanced biotransformation metabolism due to depletion of Phase II substrates and co-factors can be the first linkage in a chain of events with severe pathological outcomes. It is vital for scientific advancement and clinical applications that the phenomenon of unbalanced biotransformation metabolism be considered as a primary cause of metabolic aberrations manifesting as increased oxidative stress status. The proposed unbalanced biotransformation metabolism model will be illustrated using defective β-oxidation of fatty acids, and its value will be demonstrated by its application in the development of individualized treatment protocols for patients suffering from induced and/or inborn errors of metabolism
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