Vol.3, No.1, 43-48 (2011) Health
Copyright © 2011 SciRes. Openly accessible at http://www.scir p.org/journal/HEALTH/
Unbalanced biotransformation metabolism and
oxidative stress status: implications for deficient fatty
acid oxidation
Catharina M. Mels*, Francois H. Van der Westhuizen, Pieter J. Pretorius, Elardus Erasmus
Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa; *Corresponding Author: 12076341@nwu.ac.za
Received 11 November 2010; revised 18 November 2010; accepted 19 November 2010.
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 func-
tion of the li v er, and the critical balan ce 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 dis-
turbance in this balance will increase the oxida-
tive 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 reac-
tions, with resulting depletion of biotransforma-
tion 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 bal-
ance 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 defi-
cient fatty acid oxidation only became evident
once the critical balance between Phase I and
Phase II biotransformation was restored with
oral replenishment of biotransformation sub-
strates. In addi tion to biochemical im provement,
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 im-
balances. This in turn may reduce the chances
of, or delay the onset of certain disease states.
Keywords: Biotransformation Metabolism;
Detoxification; Fatty Acid Oxidation; Oxidative
Stress Status
The indispensable role of the liver in the biotransfor-
mation 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. Phase I reactions ex-
pose functional groups to form reactive sites, which im-
prove water solubility of the compound itself, or allow
Phase II reactions to ensue when the products of Phase I
biotransformation are conjugated with endogenous hy-
drophilic compounds to enhance their excretion [1-3].
However, during Phase I functionalization the resultant
reactive molecule can in certain cases be more toxic than
the parent compound, and effective neutralization of
these noxious compounds is important in preventing
covalent binding of the reactive metabolites to proteins,
lipids and nucleic acids [2,3].
Maintaining the balance between Phase I and Phase II
reactions is therefore of paramount importance, and un-
der normal circumstances these enzymes function ade-
quately to minimize inefficient detoxification and poten-
tial induced intracellular damage. However, an over-
loaded or unbalanced system negatively affects the
oxidative stress status, with serious health compromi sing
consequences [ 3,4].
The metabolic processes that are fundamental for
maintaining normal cell structure and fun ction are highly
regulated enzyme catalyzed processes. Defects in these
enzyme systems, whether induced or inherited, have
C. M. Mels et al. / Health 3 (2011) 43-48
Copyright © 2011 SciRes. Openly accessible at http: //www.scirp.org/journal/HEALTH/
significant consequences in man, i.e. the accumulation of
toxic substrates upstream of the enzyme defect, distur-
bances in metabolic intermediates downstream of the
enzyme defect, and the formation of intermediates by
alternative biochemical pathways [5]. On a clinical level
these biochemical aberrations will give rise to various
pathological conditions including acute life-threatening
encephalopathy, hyperammonemia, metabolic acidosis,
hypoglycemia, jaundice and liver dysfunction [6]. This
can ultimately lead to the development of chronic dis-
eases and eventual death.
Biotransformation metabolism is a well studied dis-
cipline within the pharmaceutical industry, and the con-
cept of accumulating xenobiotics within the human body
as a health risk is well known. However, the accumula-
tion of endogenous compounds in the case of inborn
errors of metabolism and its pathological consequences
is typically not explicitly associated with unbalanced
biotransformation metabolism.
Explaining the development of the phenotypic cha-
racteristics of metabolic diseases is a formidable chal-
lenge. 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 bio-
transformation 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 advan cement and clinical applications
that the phenomenon of unbalanced biotransformation
metabolism be considered as a primary cause of meta-
bolic aberrations manifesting as increased oxidative
stress status. The proposed unbalanced biotransforma-
tion metabolism model will be illustrated using d efective
β-oxidation of fatty acids, and its value will be demon-
strated by its application in the development of individu-
alized treatment protocols for patients suffering from
induced and/or inborn errors of metabolism.
In the unbalanced biotransformation metabolism
model, a hypothesis is proposed 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 con-
sequences. A defect in, or inhibition of any one of the
many enzymes involved in cellular metabolism results in
the accumulation of specific metabolites that need to be
removed from the body either via alternative pathways
or by Phase I and Phase II biotransformation metabolism.
Phase I biotransformation of accumulating metabolites
and alternative pathways, both result in additional for-
mation of reactive oxygen species (ROS). Induced Phase
I biotransformation w ill furthermore increase the burden
on Phase II conjugation and the increased demand on the
latter could lead to the depletion of conjugation sub-
strates and co-factors. Depletion of these biomolecules
will disturb the critical balance between Phase I and
Phase II biotransformation, which will further increase
the oxidative stress status, ultimately leading to the dep-
letion of the endogenous antioxidant capability, further
affecting Phase II conjugation. Increased circulating
ROS will cause oxidative damage to macromolecules
such as lipids, proteins, and nucleic acids, and some of
these adducts will contribute to the depletion of endo-
genous antioxidants. If these reactive adducts are not
neutralized effectively they can diffuse to different sites
and intensify the effects of oxidative damage by de-
creasing respiratory chain activity. This model therefore
proposes that unbalanced biotransformation metabolism
form an additional “vicious cycle” for increased oxida-
tive stress status which originates from inefficient bio-
Biotransformation metabolism is under homeostatic
regulation to control the detoxification of xenobiotics
and their metabolites. This homeostatic system includes
both negative feedback control as well as feedforward
processes. In Phase I negative feedback control, xeno-
biotics activate a range of receptors to induce Phase I
enzymes [7]. In most cases Phase I activity prepares the
arena for Phase II conjugation to take place, because the
Phase I intermediate metabolites activate transcription
factors to induce synthesis of Phase II conjugation en-
zymes, also by means of negative feedback control [2 ,3].
However, many Phase II enzymes are also upregulated
directly by the parent xenobiotic, which entails feedfor-
ward control by the reactive metabolites formed during
Phase I. This reduces the response time for the biotrans-
formation system to adapt and remove harmful Phase I
intermediates more rapidly. However, there are also oth-
er factors involved in this process, such as nutrient con-
centration control [7]. Phase I biotransformation requires
little nutritional support, whereas Phase II requires vari-
ous co-factors and substrates, which must be replenished
by dietary sources [2,3]. Therefore, although biotrans-
formation metabolism is under homeostatic regulation
which includes both negative feedback and feedforward
control, depletion of Phase II substrates and co-factors
C. M. Mels et al. / H ealth 3 (2011) 43-48
Copyright © 2011 SciRes. Openly accessible at http:/ /www.scir p.org/journal/HEALTH/
will undeniably disrupt the critical balance between
Phase I and Phase II biotransformation.
The main intracellular source of ROS is the mito-
chondrial respiratory chain. However, some enzymes
including NADPH oxidases and cytochrome
P450-dependent oxygenases also produce ROS during
their enzymatic reactions [8]. ROS normally exist in all
aerobic cells in balance with tightly controlled antioxi-
dant defence and repair mechanisms. A steady state of
oxidative stress, which is always present in cells, can
therefore increase (increased oxidative stress status) if
the endogenous antioxidant system is not capable of
coping with the continuous ROS production, or if an
uncontrolled increased ROS production occurs [9].
One of the most important endogenous antioxidant
molecules is reduced glutathione (GSH), as it plays an
important role in neutralizing free radicals. A shift in the
ratio between reduced glutathione (GSH) and oxidized
glutathione (GSSG) could therefore further increase the
oxidative stress status. In addition to its antioxidant
function, GSH is also involved in Phase II conjugation,
which can occur spontaneously or in an enzyme reaction
catalyzed by glutathione-S-transferases (GSTs) [10,11].
Compromised biotransformation can also have a great
influence on the content and type of fatty acids and ste-
roids involved in cellular signaling. Increased circulating
ROS and free fatty acids cause lipid peroxidation and the
formation of aldehyde by-products, including
4-hydroxynonenal (4-HNE) and malondialdehyde
(MDA). Detoxification of these lipid peroxidation
by-products enhances glutathione depletion even further.
If these reactive molecules are not neutralized they can
diffuse to different sites and intensify the effects of
oxidative stress by decreasing respiratory chain activity
At least 25 enzymes and transport proteins, various
co-factors, co-enzymes, and sub strates such as L -carnitine,
co-enzyme A, FAD and NAD are involved in mitochon-
drial β-oxidation, and genetic defects in at least 22 of
these proteins cause disease in humans [14-16]. In addi-
tion to inborn errors in fatty acid oxidation, various xeno-
biotic compounds can also lead to inhibited enzyme activ-
ities, e.g. Aspirin (acetylsalicylic acid), a widely used
analgesic, and Valproate (VPA), a branched-chain fatty
acid, which is clinically used in the treatment of various
seizure disorders. Acetylsalicylic acid is rapidly hydro-
lyzed to salicylic acid upon ingestion, and is then acti-
vated to salicyl-CoA before conjugation to glycine can
take place. VPA, on the other hand, undergoes the same
metabolic reactions as natural fatty acids, including mito-
chondrial β-oxidation, peroxisomal β-oxidation, and cy-
tochrome P450 dependent ω- and ω-1 hy drox yla tion [17].
Deficient mitochondrial fatty acid oxidation results in
the accumulation of free fatty acids and acyl-CoA spe-
cies [14,17]. These metabolites need to be removed from
the body either via alternative pathways, or biotransfor-
mation metabolism (Phase I and Phase II) (Figure 1).
The alternative pathway to mitochondrial β-oxidation
occurs in the peroxisomes. The first step in this pathway
is catalyzed by acyl-CoA oxidase, which involves the
reduction of oxygen to hydrogen peroxide [18-20].
Phase I biotransformation of accumulated fatty acids
involve cytochrome P450 dependent ω-oxidation of fatty
acids [21,22]. During fatty acid ω-oxidation the corres-
ponding dicarboxylic acids of the metabolized fatty ac-
ids are formed [22]. In addition, ROS is also formed
during this reaction via flavoprotein mediated donation
of electrons to molecular oxygen [23] (Figu re 1). Both
the alternative pathway and Phase I biotransformation
metabolism can therefore result in enhanced production
of ROS.
Phase II biotransformation of accumulated acyl-CoA
and Phase I generated dicarboxylic acids involve conju-
gation with either glycine or L-carnitine [14-16]. Sub-
jects with deficient fatty acid oxidation will therefore
present biochemically with elevated levels of carnitine
and glycine conjugates of acyl-CoA and dicarboxylic
acid species.
The increased demand on Phase II biotransformation
to maintain the critical balance can result in the deple-
tion of these Phase II conjugation substrates (Figure 1).
If these substrates are not replenished, the critical
balance between Phase I and Phase II biotransformation
will become disturbed. When this balance is disturbed
due to sustained induced Phase I biotransformation and
reduced Phas e II conjugation, it cou ld increase the oxid-
ative stress status [3] (Figu re 1), with a consequent shift
in the GSH:GSSG ratio, that could exacerbate the oxida-
tive stress status and affect Phase II conjugat ion [10,11].
An increased amount of circulating ROS molecules, in
addition to accumulated free fatty acids, especially
poly-unsaturated fatty acids (PUFAs), can further wor-
sen this condition, as ROS could attack these fatty acids
and initiate lipid peroxidation. Lipid peroxidation results
in the formation of aldehyde by-products, in-
C. M. Mels et al. / Health 3 (2011) 43-48
Copyright © 2011 SciRes. Openly accessible at http: //www.scirp.org/journal/HEALTH/
Figure 1. Disturbance in the critical balance between
Phase I and Phase II biotransformation metabolism by
deficient fatty acid oxidation can ultimately lead to an
increased oxidative stress status, which is the underlying
mechanism for the development of various pathologies.
cluding 4-hydroxynonenal (4-HNE) and malondialde
hyde (MDA) [12,13]. Increased presence and distribu-
tion of these peroxidized lipid metabolites could fur-
thermore lead to mitochondrial instability, as phospholi-
pids are an indispensable constituent in mitochondrial
membranes for the functional assembly of the respirato-
ry chain. The incorporation of these lipid derivatives into
mitochondria could therefore lead to decreased respira-
tory chain activity, with resulting increased oxidative
stress status [13].
Moreover, it has recently been demonstrated that two
of the accumulating free fatty acids in MCAD deficiency
(octanoate and decanoate) lead to increased oxidative
stress status [24], and the uncoupling of oxidative phos-
phorylation [25] in rat brain tissue. Unbalanced bio-
transformation metabolism and the consequent increase
in oxidative stress status are therefore a possible cause in
the development of certain neurological consequences in
these kinds of deficiencies.
In addition to an increased oxidative stress status, the
disturbed biotransformation balance can also generate
the pathological condition known as co-enzyme A (CoA)
sequestration, toxicity and redistribution (CASTOR)
[26]. This phenomenon has been demonstrated in both
inborn fatty acid oxidation deficiencies and xenobiotic
induced fatty acid oxidation deficiencies [17,26]. The
accumulation of acyl-CoA intermediates will lead to
decreased availability of free CoA and acetyl-CoA mo-
lecules, and changes in these levels can disrupt various
metabolic pathways. These metabolic pathways include
the Krebs cycle, ureagenesis, biotransformation path-
ways as well as the mitochondrial redox state. It could
also lead to further deficiencies in downstream products
within these metabolic pathways [26]. Taken together,
defective fatty acid oxidation and its concomitant bio-
chemical characteristics clearly verify the proposed un-
balance d bi otransfor mation metabolism model.
The value of the proposed model is illustrated by its
application to a clinical case investigated in our labora-
tory. A non-smoking female Caucasian, 57 years of age
presented with chronic fatigue, coughing, dyspnoea, pain
and anorexia and was diagnosed with metastatic small
cell carcinoma of the lung. The cancer also metastasized
to the liver although liver function tests were within the
reference range. After the diagnosis she was started on a
chemo combination therapy, called CAV, which consists
of Cyclophosphamide, Doxorubicin and Vincristine for
six repeated cycles over a period of twenty weeks. For
the whole assessment time she continued with a pre-
scribed medication regimen consisting of: Epilim (so-
dium valproate), Lamicton (Lamotrigine), Leponex
(Clozapine) and Simvastin (Simvastatin, ascorbic acid
and butylated hydroxyanisole).
Four weeks before the end of chemotherapy, the sub-
ject suffered from severe fatigue and the first biotrans-
formation and oxidative stress status assessments were
done. This assessment was performed by challenging
Phase I and Phase II biotransformation reactions with
appropriate pr ob e substrates. Caffeine was used as a probe
substrate for CYP1A2 activity (Phase I), and paraceta mol
and aspirin as probe substrates for glucuronide conjuga-
tion, sulfate conjugation, glutathione conjugation and
glycine conjugation (Phase II) [3]. In addition to this, the
total acylcarnitine profile and oxidative stress status pa-
rameters including the ferric reducing antioxidant power
(FRAP assay), the ROS assay, measurement of hydroxyl
radical markers like catechol and 2,3-dihydroxybenzoic
acid (2,3-DHBA) as well as the determination of total
glutathione were also included in this assessment.
From the results obtained during th e initial assessment,
it was evident that the biotransfo rmation metabolism and
antioxidant defense systems of this subject were func-
tioning below normal. The activity of Phase I (CYP1A2)
measured as the caffeine clearance value, as well as all
the measured end products for the different Phase II
conjugation reactions were also in the lower part of the
reference range, with glycine conj ugation being very low.
The measured concentration of free carnitine was just
within the reference range. The total glutathione (GSH
C. M. Mels et al. / H ealth 3 (2011) 43-48
Copyright © 2011 SciRes. Openly accessible at http:/ /www.scir p.org/journal/HEALTH/
and GSSG) concentration was low, with ROS levels and
2,3-DHBA levels being exceptionally high.
The results of this initial assessment were used to de-
velop an individualized nutritional supplementation pro-
tocol in which various compounds that can be divided
into different classes including antioxidants, mitochon-
drial support supplementation and biotransformation
substrates and co-factors were employed. After the in-
troduction of this individualized nutritional treatment
strategy, several follow-up investigations were per-
formed over a period of 7 months to monitor both bio-
chemical and clinical characteristics.
Shortly after the introduction of the nutritional sup-
plementation treatment, the Phase I activity was mar-
kedly elevated, which could lead to the formation of
more free radicals. However, after a few weeks the
Phase I activity stabilized at levels well within the ref-
erence range. All the Phase II reactions also improved,
with considerable improvement in glucuronide, sulfate
and glutathione conjugation. Although the glycine con-
jugation also improved, values remained just below or
just within the reference range. In addition to this the
total available glutathione and the serum FRAP also in-
creased with concomitant decreased ROS and
2,3-DHBA concentrations. The amount of free carnitine
increased substantially after only eight w eeks of starting
the supplementation regimen. However, the ratio be-
tween acylcarnitines and free carnitine was slightly ele-
vated. After careful investigation of the total acylcarni-
tine profile, the source of the elevated ratio between
acylcarnitines and free carnitine in these assessments
was due to increased levels of medium-chain acylcarni-
tines and medium- chain dicarboxylcarnitines, including
hexanoylcarnitine, octanoylcarnitine, adipylcarnitine and
It is evident in this case that the biotransformation and
antioxidant defense systems were initially markedly
compromised. The identification of the accumulated
metabolites usually seen in fatty acid o xidation deficien-
cies is the most significant observation in this regard.
Initial concentrations of Phase II substrates were so dep-
leted that these metabolites were only observed after oral
replenishment of the main conjugation substrate. Once
the critical balance between Phase I and Phase II bio-
transformation was restored, the oxidative stress status
decreased to levels within the reference range. In addi-
tion to the biochemical improvement, the subject also
showed a significa nt clinical improvement, and although
these results are only preliminary, it supports the value
of the proposed unbalanced biotransformation metabol-
is m mo del.
The significance in testing this model lies within the
treatment possibilities, no t only for inborn errors of fatty
acid metabolism, but also for induced fatty acid oxida-
tion deficiencies. It can furthermore also be significant
in various metabolic aberrations manifesting as in-
creased oxidative stress status. If the disturbance in this
critical balance is indeed the first link in a chain of reac-
tions to follow, which ultimately lead to pathological
conditions like cancer, the assessment of these reactions
is of immense importance. This kind of assessment can
lead to the development of individualized treatment pro-
tocols to replenish important substrates and co-factors
needed for the safe elimination of accumulated toxic
This work has been funded by BioPAD, Program 1: Metabolome anal-
ysis (Subprogram 1.3). We would like to thank Dr J. L. Duminy at
Wilmed Park Oncology Cen tre, Klerksdorp, South Africa for the clini-
cal evaluation and input in the case involved.
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