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Xenobiotic Metabolism and The Mechanism(s) of Benzene Toxicity
Xenobiotic Metabolism and The Mechanism(s) of Benzene Toxicity
of Benzene Toxicity
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,
Piscataway, New Jersey, USA
ABSTRACT
For personal use only.
*Correspondence: Robert Snyder, Ph.D., Associate Dean for Research, Ernest Mario School of
Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
531
INTRODUCTION
The student training in toxicology is faced with a wide variety of career choices
ranging from risk assessment, in either government or industry; laboratory-based
toxicological or carcinogenic evaluation; clinical and forensic toxicology; toxicological
consulting to non-toxicologically oriented professionals or the lay public; and basic
mechanistic research in toxicology. Most of toxicology is concerned with either
describing the effects of exposure to a chemical or to the prediction of effects that will
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occur in the future. Mechanistic studies are aimed at determining why the observed
effects occurred and are framed around specific questions (hypotheses) aimed at
extending our current understanding, usually by taking advantage of the newest
technology. As a result, a mechanism described 20 years ago may today appear to be a
superficial observation in need of greater in-depth analysis because both the database
and the technology have been enhanced. As the state of the art changes, the definition
of ‘‘mechanism’’ changes.
Students who enter the fields of Biochemical Pharmacology and Toxicology today
plunge into the realms of the ‘‘omics,’’ i.e., genomics, proteomics, metabonomics, etc.,
which represent the most recently developed advanced technologies in biology. It is
inherent in the ‘‘omics’’ technologies that their application results in more data than we
have been able to deal with and as a result have given rise to a new field called
For personal use only.
Informatics. Thus, students about to study the new biology will have little opportunity
to examine or appreciate the existing data base that their work will enhance. This
review is intended to provide a brief synopsis of developments in the field of
xenobiotic metabolism as they have impacted on the developing area of Mechanistic
Toxicology using the study of the mechanism(s) of benzene toxicity as a case in point.
The history of occupational toxicology goes back into antiquity (Hunter, 1962).
The most famous compilation relating the activities of working people with diseases
was De Morbis Artificum Diatriba (A Discourse on the Diseases of Workers) by
Bernardino Ramazzini published in 1700 (Ramazzini, 1964). However, it was not until
the late 19th and early 20th centuries that a clear association between specific disease
entities and exposure to specific chemicals was recognized. Santesson (1897), in
describing several cases of a disease referred to as purpura hemorrhagica, claimed that
exposure to benzene in the workplace was ‘‘. . .das wesentlich toxische Princip. . .’’ i.e.,
‘‘. . .the intrinsic toxic principle. . .’’ responsible for the disease. His report stimulated a
body of research aimed at defining the diseases we now associate with benzene
exposure, uncovering the mechanisms by which these effects are produced, and
creating safer workplaces by control of benzene exposure.
The recognition that the workplace environment was related to specific disease
entities led to many studies, in the early 20th century, which described the effects
produced by simulated workplace exposures in animal models, while more carefully
delineating the effects observed in exposed workers using the methods of the
developing discipline of occupational epidemiology. However, it was not until the post-
WWII era that significant advances were made in understanding the underlying
mechanisms by which chemicals caused adverse health effects. It was no coincidence
that it was during this time that our understanding of xenobiotic metabolism expanded
exponentially. It is especially appropriate to recall these events in a volume dedicated
Xenobiotic Metabolism and the Mechanism(s) of Benzene Toxicity 533
to Prof. Dr. Herbert Remmer, the late Director of the Institute of Toxicology at the
University of Tübingen in Germany.
XENOBIOTIC METABOLISM
metabolism (Keilin, 1966; Lipmann, 1971; Warburg, 1966). Kornberg (1989) has
described these times as the eras of the ‘‘vitamin hunters’’ and the ‘‘enzyme hunters.’’
A full appreciation of intermediary metabolic pathways, however, was not possible
until the 1940’s – 1960’s when radiolabeled substrates became available.
By the same token, studies on the metabolism of xenobiotic chemicals prior to
WWII were hampered by the lack of methods for separating and measuring both the
starting chemicals and their metabolites. Studies by J. A. Shannon, B. B. Brodie, S.
Udenfriend and their colleagues on anti-malarials emphasized the need for adequate
analytical chemical methodology (Kanigel, 1986) but did not solve the problem of
the need for highly sensitive methods for the measurement of chemicals at low
concentrations. One of the early examples of the use of radiolabeled xenobiotics to
explore metabolic pathways with high sensitivity occurred when Professor R. T.
For personal use only.
Williams asked his student, Dennis Parke, to synthesize [14C]benzene, feed it to rabbits,
and examine the metabolites in urine, feces, and the expired air (Parke, 1996; Parke
and Williams, 1953). This path finding study provided the basis for our current
understanding of the pathway of benzene metabolism
Characterization of the enzyme systems responsible for xenobiotic metabolism,
involved the demonstration of the incorporation of atmospheric molecular oxygen into
chemical substrates by Mason (1957) and Hayaishi (1962), and the observation of a
CO-binding pigment in hepatic microsomes by Klingenberg (1958) and Garfinkel
(1958), which was shown to be a heme-protein. The CO-binding pigment was called
cytochrome P450, by Omura and Sato (1962), and was demonstrated to be the oxygen
activating enzyme in xenobiotic metabolism in the laboratory of Estabrook et al. (1963)
and Cooper et al. (1967).
There was clearly a relationship between cytochrome P450, now frequently
referred to as CYP (a family of enzymes rather than a single enzyme) and both
pharmacological and toxicological processes. Thus, the demonstration by Brodie and
Axelrod (Axelrod, 2003) that acetanilide was effective as an analgesic because it was
metabolized to acetaminophen was a clear example of the significance of CYP in
metabolic activation of a prodrug to an effective drug. By the same token, James and
Elizabeth Miller (1977) demonstrated the need for metabolic activation to convert
aromatic amines, safrole, and aflatoxin B1 to carcinogenic electrophilic metabolites.
The critical observations that potentiated the role of metabolism in the examination
of mechanisms of toxicity arose from the findings that activity of the CYP enzyme
system could be altered by environmental factors, the most important of these having
been the discovery of the phenomenon termed ‘‘enzyme induction.’’ As reviewed in
detail elsewhere (Conney, 2003; Snyder, 2000; Snyder and Remmer, 1979), treatment
of animals with any of a wide variety of chemicals, the most prominent of which in
534 Snyder
concentrations as measured by the height of the CO-binding spectral peak at 450 nm.
The report of Alavares et al. (1967) showed a CO-binding peak at 450 nm following
barbiturate induction and 448 nm following PAH induction, suggesting that there were
at least two forms of CYP.
The critical experiments needed to settle the discussion were the isolation and
characterization of the CYP enzyme system that is bound into the membranes of the
SER. A method was required that would disrupt the membranes and free the enzymes
but allow them to retain their activities. Lu and Coon (1968) treated hepatic
microsomes with a detergent (desoxycholate) and separated three components of the
CYP system by column chromatography, i.e., cytochrome P450, NADPH cytochrome
P450 reductase, and a lipid essential for restoration of CYP activity after the system
was reconstituted. The heme protein was the site at which the substrate and molecular
oxygen interacted to yield the product, the reductase insured a sufficient level of
reducing equivalents [NAD(P)H] to maintain the heme in its reduced (Fe++) form
necessary for it to bind with oxygen, and the lipid provided a mechanism for
maintaining a structural association among the components. Since that time CYP
enzyme systems have been reported throughout biology. Keeping track of them has
been aided by computerized databases such as the Cytochrome P450 Home Page
(http://dnelson.utmem.CytochromeP450.html), which suggests that there are thousands
of CYP enzymes among biological species, and the Home Page of the Human
Cytochrome P450 Allele Nomenclature Committee (wysiwyg://10/http://imm.ki.se/
CYPalleles/), which lists 20 files for human CYP alleles.
Although the metabolism of chemicals may lead to detoxication, the principal
interest of toxicologists in xenobiotic metabolism has been metabolic activation to
biological reactive intermediates. Miller and Miller (1966) proposed that the
metabolism of carcinogens results in detoxication or conversion to ultimate
carcinogens, sometimes after passing through a stage in which they are referred to
Xenobiotic Metabolism and the Mechanism(s) of Benzene Toxicity 535
inducibility and the formation of biological reactive intermediates, that the study of the
association between benzene metabolism and benzene toxicity has been investigated.
BENZENE TOXICITY
Extensive descriptions of benzene toxicity appear in the literature and need not be
repeated here in detail (Snyder, 2002; Snyder and Kocsis, 1975; Snyder and Kalf,
1994). In brief, chronic exposure to benzene vapor results in anemia, various forms of
leucopenia, and/or thrombocytopenia. Early detection of reductions in circulating blood
cell levels and prevention of further exposure may lead to restoration of normal blood
cell levels, but continued exposure may lead to greater decreases in cell numbers
For personal use only.
BENZENE METABOLISM
Although it was recognized for many years that benzene could be converted in vivo
to phenolic metabolites, the path finding studies of Parke and Williams (1953), and
subsequent work in the Williams laboratory, permitted a delineation of the metabolic
pathway for benzene, which for the most part is still accepted. Benzene travels
to the liver where it undergoes epoxidation (Jerina and Daly, 1974) by CYP2E1. The
resulting benzene oxide establishes an equilibrium with its oxepin or may rearrange
536 Snyder
involves the conjugation of benzene oxide with glutathione as the first step in a
pathway that ultimately results in the formation of phenyl mercapturic acid. The
benzene ring can be opened either at the benzene oxide or oxepin stage with the
resulting formation of muconaldehyde (Goldstein et al., 1982). An indicator for t,t-
muconaldehyde formation would be the appearance of t,t-muconic acid in the urine.
The hydroxylated metabolites may appear in the urine as either ethereal sulfate or
glucuronide conjugates.
In parallel, with contemporaneous studies of xenobiotic metabolism in hepatic
microsomes, we elected to examine benzene metabolism in vitro using [14C] or [3H]
benzene and found that benzene could be metabolized in liver preparations (9,000 g
liver supernatants, or microsomes) from rabbits, mice and rats (Snyder et al., 1967).
The hydroxylating enzyme appeared to be a member of the CYP family of enzymes
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(Gonasun et al., 1973; Saito et al., 1970). The metabolism could be enhanced if the
animals were pretreated with either benzene or phenobarbital, but not by beta-
naphthoflavone (Post and Snyder, 1983a). The phenobarbital- and benzene-induced
benzene hydroxylases displayed different properties, e.g., pH optimum, KM. Witmer et al.
(1971) originally observed an increase in benzene metabolism in liver microsomes
upon the addition of fluoride. Post and Snyder (1983b) demonstrated that the fluoride
effect was observed following induction with benzene, but not with phenobarbital. These
observations in microsomal preparations were supported by studies of benzene metab-
olism in purified, reconstituted preparations of phenobarbital-induced CYP4502B1, and
isoniazid-induced CYP4502E1. Thus, Post and Snyder (1983b) suggested that the KM
value for the benzene-induced enzyme was 10-fold lower than for the phenobarbital-
induced enzyme. In the isolated enzyme system, the value for CYP2E1 was 0.71 mM for
benzene and 0.08 for phenol. The values reported for CYP2B1 by Gorsky and Coon
(1985) was 105 mM whereas Griffiths et al. (1986) reported a value of 13.2 mM for a
reconstituted preparation of CYP2B1.
In studies aimed at examining the metabolic pathway of benzene using the
reconstituted rat liver CYP2E1 system (Snyder et al., 1993), it was demonstrated that
the presence of cytochrome B5 enhanced benzene metabolism. The addition of purified
epoxide hydrolase stimulated the production of hydroquinone raising the possibility that
rat liver CYP2E1 might, to some extent, generate benzene-1, 4-epoxide in addition to
benzene-1,2-epoxide.
Mice are more susceptible to benzene toxicity than rats (Sammett et al., 1979) and
the array of benzene metabolites in the urine of benzene-treated mice (Snyder et al.,
1982) is more complex than found in the urine of benzene-treated rats (Bakke and
Scheline, 1970). Thus, it would have been useful to examine benzene metabolism in a
reconstituted CYP2E1 system from the mouse, but that enzyme was not then available.
Xenobiotic Metabolism and the Mechanism(s) of Benzene Toxicity 537
increased and eight of these metabolites accounted for 90% of the metabolism. In a
collaborative effort, we compared benzene metabolism in rat hepatocytes with that in
mouse hepatocytes and found that mice produced more polyhydroxylated metabolites,
and high levels of hydroquinone sulfate, and 1,2,4-benzenetriol sulfate (Orezchowski
et al., 1995).
The appearance of greater amounts of potentially more toxic metabolites in mouse
hepatocytes was suggested as the basis for the higher degree of susceptibility to
benzene in the mouse than the rat. However, it was recognized that incubating the
substrates and their metabolites for several hours, without the capability of metabolites
being carried away in the circulation, was sufficiently unphysiological to require
confirmation in a system which permitted products to be separated from the cells. As a
result, we examined benzene metabolism (Hedli et al., 1997) and phenol metabolism
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(Hoffmann et al., 1999) in the isolated, perfused mouse liver (Hedli, 1999; Hedli et al.,
1997). The results suggest that benzene metabolism, and fate of its metabolites, depend
upon its perfusion through the liver and entry into hepatocytes, and the ability of
metabolites to leave the hepatocytes, enter the circulation, and exit from the liver by
via the venous system. Metabolites leaving the liver after a single pass include both
conjugated and unconjugated phenolics. Both the degree of hydroxylation among the
metabolites and the extent of conjugation increases as the blood recirculates through
the liver. Since the CYP2E1 system is concentrated in the region of the hepatic triad
close to the central vein, benzene, upon entering the triad, bypasses much of the
conjugating system and is hydroxylated close to the point of exit from the liver. As a
result, unconjugated metabolites were found in the exiting perfusate, and might,
therefore, contribute to bone marrow toxicity. Alternatively, re-perfusion as the blood
recirculates through the liver leads to both repeated hydroxylations and to more com-
plete conjugation. The possibility remains that conjugated polyhydroxylated metabo-
lites in the circulation might contribute to toxicity if they reach the bone marrow at
concentrations sufficiently high to approach the KM values for hydrolytic enzymes and,
thereby, release active quinone precursors such as hydroquinone or catechol.
The search for one or more mechanisms of toxicity began with the hypothesis that
toxicity was related to the production of one or more of the following metabolites:
phenol, hydroquinone (and by extension, p-benoquinone), catechol (and by extension,
o-benoquinone), 1,2,4-benzenetriol, and muconaldehyde.
538 Snyder
synthesis. Thus, the method involved sampling the reticulocyte pool in mice or rats by
administering 59Fe, waiting 24 hours while the reticulocytes matured to erythrocytes,
and measuring red cell iron incorporation. The entire assay could be completed within
several days rather than the several months required to observe bone marrow effects
due to benzene exposure by inhalation.
Administration of benzene, or benzene metabolites, inhibited erythropoiesis and the
most sensitive cells were the pronormoblasts (Lee et al., 1974). The 59Fe uptake
method was used to show that benzene metabolism was required to produce benzene
toxicity. Thus, inhibition of benzene metabolism by toluene (Andrews et al., 1977), and
reduction of benzene metabolism in partially hepatectomized rats or mice (Sammett
et al., 1979), protected against benzene toxicity.
Application of the 59Fe uptake method permitted us to demonstrate the relative
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It is noteworthy that there have been many reports of covalent binding of benzene
metabolites to proteins in vitro (Snyder, 2002). In several reports, specific proteins were
examined and it was suggested that interaction with metabolites such as hydroquinone (or
p-benzoquinone) may be closely related to the mechanism of benzene-induced bone
marrow damage, e.g., mtDNA polymerase (Schwartz et al., 1985), topoisomerase II
(Chen and Eastmond, 1995; Hoffmann et al., 2001a; Hutt and Kalf, 1996), calpain-
mediated conversion of pre-interleukin-1a to interleukin-1a (Nicolescu et al., 1995),
which will be discussed below. Non-enzymatic protein interactions include inhibition of
tubulin function (Irons et al., 1981) and protein-DNA cross linking (Schoenfeld and Witz,
2000). Despite the emphasis placed on studies of binding of benzene metabolites to
DNA, covalent binding of benzene metabolites to proteins may be highly significant in
defining the mechanisms of both benzene toxicity and benzene-induced leukemogenesis.
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CONCLUSIONS
mechanism of toxicity, especially when the metabolic pathway described occurs in liver
and the toxic effects occur in bone marrow. Furthermore, the toxic effects appear to
involve mechanisms of cell death which may include apoptosis or necrosis. The
leukemogenic effects appear to be related to alteration of differentiation and maturation
of cells in the bone marrow. There is clearly disruption of normal chromosome
structure (Smith et al., 1998; Zhang et al., 1998); and it has yet to be decided whether
chromosome damage is the cause or the result of benzene exposure. Since chromosome
aberrations are associated with a number of types of leukemias, it is attractive to
suggest a direct link between the two phenomena, but specifics of that linkage have yet
to be determined (Snyder, 2002).
Hopefully, application of genomics, proteomics, and informatics will provide an
approach to the study of benzene-induced bone marrow damage which was not possible
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with the limited technologies of the past several decades. For example, in a recent
study by Yoon et al. (2003) that dysfunction of the p53 gene caused by ‘‘strong and
repeated genetic and epigenetic effects of benzene,’’ might impact on cell cycle
checkpoints and apoptosis leading to malignant transformation to leukemic cells. This
is clearly the beginning of a new phase in the study of the mechanism(s) of benzene
toxicity/leukemogenesis and once again suggests that we must refocus our thoughts on
the definition of the word ‘‘mechanism’’ in the face of emerging technologies which
will permit us to ask questions more relevant to 21st century toxicology.
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