Handbook of Solvents - George Wypych - ChemTech - Ventech!

1384 Nachman Brautbar
Table 20.7.4. Phase II (conjugation) reactions. [Adapted by permission, from HJ
Zimmerman, Hepatotoxicity, 1978]
Type of conjugation
Glucuronidation
Dihydrodiol formation Water
GSH conjugation GSH
Endogenous
substance
UDP-glucuronic
acid
Transferring enzyme and
location
UDPG-transferase
(microsomes)
(Epoxide) hydrase
(cytosol)
GSH-S-transferase
(cytosol)
Type of xenobiotics & metabolites
conjugated
Phenols; alcohols; carboxylic acids;
primary amines; hydroxylamines;
sulfonamides, etc.
Epoxides and arene oxides
Epoxides; arene oxides; halides; nitro
groups; hydroxylamines, etc.
Glycine conjugation Glycine
Acyl CoA-glycine
transferase (mitochondria)
CoA derivatives of carboxylic acids
Sulfate conjugation PAP-sulfate Sulfotransferase (cytosol) Phenols; alcohols; aromatic amines
Methylation
S-adenosylmethionine
Transmethylase (cytosol)
Catechols; phenols; amines;
histamine
The carcinogenic effect of carbon tetrachloride will not be discussed in this chapter,
and the reader is referred to other texts. 22
20.7.2 INDIVIDUAL VARIABILITY AND HEPATOTOXICITY OF SOLVENTS
The issue of individual variability based on various factors as described above is important,
especially in medical monitoring and risk assessment in occupationally exposed patients.
The fact that workers in industrial environments are not the same and are subject for differences
such as body build, underlying kidney function differences (genetic or acquired), exposure
to other solvents or other liver toxicants may effect the results. A recent study 23
evaluated a population response to solvent exposure. These investigators have shown that
body fat is the most important body compartment for fat soluble solvents. Body fluids and
physical work load effect the blood flow, alveoli ventilation and therefore will effect the
amount of solvent inhaled as well as absorbed through the blood and delivered to the liver.
They have developed the physiological model which takes into account variability in the
form of exposure, physical overload, body build, liver function and renal function. Other
factors which have been taken into account are solubility in blood and tissue. Investigators
suggested that such a model should be useful in improving our understanding of the complex
and multifactorial system and to generate a hypothesis, and to improve our assessment
of occupational exposure. This has significance from a clinical toxicology point of view. A
patient who has an increased body fat will be at a higher risk of solvent toxicity. If this same
patient also has a habit of heavy alcohol consumption the risk for solvent liver toxicity is
significantly increased. Epidemiological studies are commonly not designed to evaluate the
individual hepatotoxicity of solvents and therefore the issue of cause and effect must be
viewed taking into account individual variability, other risk factors, and medical common
sense, following the well established criteria by practitioners of medicine.
Chloroform is another haloalkane which has been typically used as an example to understand
and study the toxic effects on the liver. Studies in experimental animals in 1866 24
have shown that the chloroform causes liver toxicity. In 1923 Meyer et al. 14 have shown that