|Lecture Notes:: 23 March
© R. Paselk 2008
- Aniline may be metabolized into either para- or ortho-hydroxyl compounds:
The preferred route of hydroxylation varies significantly, and correlates with toxicity. Thus species which produce more o-aminophenol (e.g. cats and dogs), which is more toxic, are more sensitive to aniline than those which produce more p-aminophenol (e.g. rats and hamsters). Species differences in aniline hydroxylation are compared in Table 5.9, p 139 of Timbrell 4th.
- Malathion is an example where people have taken advantage of species differences in metabolism. Malathion is a relatively low toxicity compound which is metabolized quite differently by mammals and insects:
Malaoxon is a potent cholinesterase inhibitor, and thus acts as a neurotoxin for insects, while the diacid is excreted after conjugtion by mammals with little harm.
- Amphetamine metabolism is another compound where there are significant differences in terms of metabolic product, as shown in the figure below:
- Additional examples include species differences in hexobarbital metabolism as seen in Table 5.10, p 140 of Timbrell 4th., and hepatic reductase activities in various species as seen in Table 5.11, p 142 of Timbrell 4th.
Variations in Absorption, Distribution, and Excretion of compounds.
- Skin penetration vs. Toxicity of Organophosphorous Compounds. (overhead - Table 5.2, p 135)
- Salivary and Gastric pH. (overhead - Table 5.3, p 135)
- Binding of Plasma Proteins. (overhead - Table 5.4, p 136)
- Biliary Excretion. (overhead - Table 5.7, p 137)
- Urinary Volume and pH. (overhead - Table 5.5, p 136)
- Note scaling as possible explanation.
- Urinary Excretion. (overhead - Table 5.6, p 137)
- Note scaling as possible explanation.
Strain/genetic variations in toxicity
An important example of strain/genetic variation in toxicity is seen in the differences between so-called fast and slow acetylators as shown in Figure 5.23 (p 153) and tables 5.14 (p 152) & 5.16 (p 155) of Timbrell 4th.
Physiological Factors & Toxicology
Stress can have a variety
of effects on health and on toxin metabolism. For example, cold
stress and excess noise both increase the hydroxylation of aromatic
Diet can have a diverse
impact on xenobiotic metabolism. Variations in enzyme expression
can have particular impacts:
- Particular foods and/or food balance can induce enzyme production
(due to food or food additives - repeated doses needed).
- Foods and/or food additives can cause enzyme inhibition (single
dose can be effective).
Both enzyme induction and inhibition can in turn have diverse
and unexpected results:
- Can see reduced toxicity due to increased processing (higher
- Can see increased toxicity due to increased processing (higher
- Can see increased toxicity due to decreased conjugation of
Enzyme induction can often result in remarkably specific changes
as a result of the new spectrum of enzyme activities.
As a result prediction of the effects of inducers requires
a good deal of prior knowledge regarding the xenobiotic's metabolism
as well as the enzyme induced.
Inhibitors on the other hand can display considerable specificity
for tissues and effects (e.g. neurotoxicity due to neuron receptor
Nutritional status can also effect toxin action. For example,
the lack of a nutrient can have both positive and negative effects.
- For example, consider low protein:
- As measured in vitro microsomal enzyme activities
are decreased >2-fold when going from a 20% protein diet to
a 5% protein diet. (Barbiturate sleeping times are in agreement
with these in vitro results, supporting the 2-fold effect.)
- Carbon tetrachloride is less toxic (due to its lowered metabolism).
- Paracetamol is increased in toxicity (due to a reduction
- Aflatoxin has a decrease in carcinogenicity (because there
is less formation of the active epoxide).
- Serum protein concentrations decrease, which can affect toxin
binding, and thus thresholds for some toxins.
Last modified 23 March 2010
© RA Paselk 2001