5.8.2 FASTING AND STARVATION
Fasting or starvation, the most severe forms of nutritional modulation,
influence xenobiotics toxicity in such a way that they may cause depressed
metabolism and so reduced clearance of chemical agents. Consequently,
increased toxicity may be seen.
Studies with animals have shown that the effect of fasting on microsomal
oxidase activity is species-, substrate-, and sex-dependent. For instance, some
reactions are decreased in male rats but increased in female rats, while others
may not be affected at all. It is thought that the sex-dependent effect is related
to the ability of androgen to enhance binding of some substrates to cytochrome
P450. Animal studies also showed that glucuronide conjugation was decreased
under starvation.
5.8.3 PROTEINS
The effects of proteins on the toxicity of environmental chemicals include both
quantitative and qualitative aspects. Laboratory animals fed low-protein diets
and exposed to toxicants often show higher toxic effects than observed in
animals fed normal-protein diets. Protein deficiency causes hypoproteinemia
and impaired hepatic function, leading to decreased levels of hepatic proteins,
DNA, and microsomal P450, as well as lowered plasma binding of xenobiotics.
Plasma contains many different proteins, such as albumin, glycoprotein, and
lipoprotein. Albumin, in particular, has an important role in the binding and
distribution of xenobiotics in the body, and so lowered binding of xenobiotics
by plasma albumin could result in greater toxicity.
Protein deprivation may impair the metabolism of toxicants that occur in
the body. Increased toxicity of chemical compounds and drugs in protein
deficiency has long been known. The toxicity of most pesticides, such as
chlorinated hydrocarbons, herbicides, fungicides and acetylcholinesterase
(AChE) inhibitors, is increased by protein deficiency (Table 5.3). In a recent
study, Tandon et al.
17 showed that the activities of the antioxidant enzymes,
including superoxide dismutase (SOD), glutathione (GSH) peroxidase
(GSHPx), and catalase, were decreased in rats fed a low-protein diet
(containing 8% protein). Furthermore, the rats showed significantly increased
levels of lipid peroxidation.
Alteration of xenobiotic metabolism by protein deprivation may lead to
either enhanced or decreased toxicity, depending on whether the metabolites
are more or less toxic than the parent compounds. The results shown in Table
5.3 reveal that low protein diets can cause decreased metabolism but increased
mortality with respect to the chemicals concerned. In contrast, rats treated
under the same conditions showed a decrease in mortality with respect to
heptachlor, CCl 4 , and aflatoxin B 1 (AFB 1 ), a toxin produced by Aspergillus
flavus. It is known that heptachlor and AFB 1 are metabolized in the liver to
their respective epoxide forms (Figure 5.2 and Figure 5.3), which are more
toxic than the parent substances. For example, the epoxide form of AFB 1 ,
Factors Affecting Xenobiotic Action
73
[16:54 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-005.3d]
Ref: 4365 MING-HO YU Chap-005 Page: 73 65-84
Fasting or starvation, the most severe forms of nutritional modulation,
influence xenobiotics toxicity in such a way that they may cause depressed
metabolism and so reduced clearance of chemical agents. Consequently,
increased toxicity may be seen.
Studies with animals have shown that the effect of fasting on microsomal
oxidase activity is species-, substrate-, and sex-dependent. For instance, some
reactions are decreased in male rats but increased in female rats, while others
may not be affected at all. It is thought that the sex-dependent effect is related
to the ability of androgen to enhance binding of some substrates to cytochrome
P450. Animal studies also showed that glucuronide conjugation was decreased
under starvation.
5.8.3 PROTEINS
The effects of proteins on the toxicity of environmental chemicals include both
quantitative and qualitative aspects. Laboratory animals fed low-protein diets
and exposed to toxicants often show higher toxic effects than observed in
animals fed normal-protein diets. Protein deficiency causes hypoproteinemia
and impaired hepatic function, leading to decreased levels of hepatic proteins,
DNA, and microsomal P450, as well as lowered plasma binding of xenobiotics.
Plasma contains many different proteins, such as albumin, glycoprotein, and
lipoprotein. Albumin, in particular, has an important role in the binding and
distribution of xenobiotics in the body, and so lowered binding of xenobiotics
by plasma albumin could result in greater toxicity.
Protein deprivation may impair the metabolism of toxicants that occur in
the body. Increased toxicity of chemical compounds and drugs in protein
deficiency has long been known. The toxicity of most pesticides, such as
chlorinated hydrocarbons, herbicides, fungicides and acetylcholinesterase
(AChE) inhibitors, is increased by protein deficiency (Table 5.3). In a recent
study, Tandon et al.
17 showed that the activities of the antioxidant enzymes,
including superoxide dismutase (SOD), glutathione (GSH) peroxidase
(GSHPx), and catalase, were decreased in rats fed a low-protein diet
(containing 8% protein). Furthermore, the rats showed significantly increased
levels of lipid peroxidation.
Alteration of xenobiotic metabolism by protein deprivation may lead to
either enhanced or decreased toxicity, depending on whether the metabolites
are more or less toxic than the parent compounds. The results shown in Table
5.3 reveal that low protein diets can cause decreased metabolism but increased
mortality with respect to the chemicals concerned. In contrast, rats treated
under the same conditions showed a decrease in mortality with respect to
heptachlor, CCl 4 , and aflatoxin B 1 (AFB 1 ), a toxin produced by Aspergillus
flavus. It is known that heptachlor and AFB 1 are metabolized in the liver to
their respective epoxide forms (Figure 5.2 and Figure 5.3), which are more
toxic than the parent substances. For example, the epoxide form of AFB 1 ,
Factors Affecting Xenobiotic Action
73
[16:54 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-005.3d]
Ref: 4365 MING-HO YU Chap-005 Page: 73 65-84