small molecules are freely filtered, while large molecules, such as certain
proteins, are restricted. Filtration of anionic molecules is likewise more
restricted than filtration of neutral or cationic molecules of the same size.
Toxicants that neutralize or decrease the number of fixed anionic charges on
glomerular structural elements will impair the charge- or size-selective properties of the glomerulus, leading to urinary excretion of polyanionic or highmolecular-weight proteins.
4
Environmental chemicals, including metals and drugs, may be transported
across proximal tubular cells, i.e., from renal capillaries across tubular cells to
be excreted in tubular lumena or vice versa. Many cationic substances are
excreted against concentration gradients at rates greater than the glomerular
filtration rate. This indicates an active-transport process. Such a process
requires expenditure of energy derived from oxidative metabolism carried out
in mitochondria. However, active transport that has the capability of
concentrating absorbed material may concentrate potential nephrotoxins as
well as essential substances in the renal cortex. The same toxins that cause
adverse effects on energy metabolism will impede the cellular transport of
essential solutes. Other toxic substances may also be concentrated in the
medulla.
As noted previously, metabolism of chemicals within the kidney may
produce substances that are either more or less toxic than the parent chemical.
For instance, trichloromethane (CHCl 3 ) and CCl 4 may be biotransformed into
reactive, toxic products that bind covalently to renal tissue, leading to
membrane injury. Exposure to certain other substances may result in activation
or enhancement of enzyme systems, such as the mixed-function oxidase
(MFO). The toxicity of methoxyfluorane, for example, may be enhanced as a
result of increased metabolism, as the metabolic products, i.e., fluoride and
oxalate, are both known to be potentially toxic to the kidney. Fluoride ions are
toxic to cell membranes, whereas oxalate may accumulate within the lumena of
nephrons.
Heavy metals, such as Pb, Cd, and Hg, are known also to cause renal
disease. The adverse effects of Pb may be both acute and chronic. Cells of the
proximal tubules are most severely affected, as shown by reduction in
resorptive function of nutrients such as glucose and amino acids. Conversely,
the effect of inorganic Cd salts on the kidney is largely chronic. The
characteristics of Cd nephropathy include increased Cd in the urine,
proteinuria, aminoaciduria, glucosuria, and decreased renal tubular reabsorption of phosphate. With chronic exposure to toxic levels, renal tubular
acidosis, hypercalciuria, and calculi formation occur.
5
Hg is known to produce different effects on kidneys, depending on the
biochemical form of the metal and nature of exposure. Inorganic Hg
compounds can cause acute tubular necrosis, whereas chronic low-dose
exposure to mercuric salts or elemental Hg vapor may induce an immunologic
glomerular disease. The presence of proteins rich in cysteine may be able to
alleviate Hg toxicity. As noted in Chapter 5, Se is known to antagonize Hg,
reducing its toxicity.
Defense Responses to Toxicants
107
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Ref: 4365 MING-HO YU Chap-007 Page: 107 99-110
proteins, are restricted. Filtration of anionic molecules is likewise more
restricted than filtration of neutral or cationic molecules of the same size.
Toxicants that neutralize or decrease the number of fixed anionic charges on
glomerular structural elements will impair the charge- or size-selective properties of the glomerulus, leading to urinary excretion of polyanionic or highmolecular-weight proteins.
4
Environmental chemicals, including metals and drugs, may be transported
across proximal tubular cells, i.e., from renal capillaries across tubular cells to
be excreted in tubular lumena or vice versa. Many cationic substances are
excreted against concentration gradients at rates greater than the glomerular
filtration rate. This indicates an active-transport process. Such a process
requires expenditure of energy derived from oxidative metabolism carried out
in mitochondria. However, active transport that has the capability of
concentrating absorbed material may concentrate potential nephrotoxins as
well as essential substances in the renal cortex. The same toxins that cause
adverse effects on energy metabolism will impede the cellular transport of
essential solutes. Other toxic substances may also be concentrated in the
medulla.
As noted previously, metabolism of chemicals within the kidney may
produce substances that are either more or less toxic than the parent chemical.
For instance, trichloromethane (CHCl 3 ) and CCl 4 may be biotransformed into
reactive, toxic products that bind covalently to renal tissue, leading to
membrane injury. Exposure to certain other substances may result in activation
or enhancement of enzyme systems, such as the mixed-function oxidase
(MFO). The toxicity of methoxyfluorane, for example, may be enhanced as a
result of increased metabolism, as the metabolic products, i.e., fluoride and
oxalate, are both known to be potentially toxic to the kidney. Fluoride ions are
toxic to cell membranes, whereas oxalate may accumulate within the lumena of
nephrons.
Heavy metals, such as Pb, Cd, and Hg, are known also to cause renal
disease. The adverse effects of Pb may be both acute and chronic. Cells of the
proximal tubules are most severely affected, as shown by reduction in
resorptive function of nutrients such as glucose and amino acids. Conversely,
the effect of inorganic Cd salts on the kidney is largely chronic. The
characteristics of Cd nephropathy include increased Cd in the urine,
proteinuria, aminoaciduria, glucosuria, and decreased renal tubular reabsorption of phosphate. With chronic exposure to toxic levels, renal tubular
acidosis, hypercalciuria, and calculi formation occur.
5
Hg is known to produce different effects on kidneys, depending on the
biochemical form of the metal and nature of exposure. Inorganic Hg
compounds can cause acute tubular necrosis, whereas chronic low-dose
exposure to mercuric salts or elemental Hg vapor may induce an immunologic
glomerular disease. The presence of proteins rich in cysteine may be able to
alleviate Hg toxicity. As noted in Chapter 5, Se is known to antagonize Hg,
reducing its toxicity.
Defense Responses to Toxicants
107
[16:53 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-007.3d]
Ref: 4365 MING-HO YU Chap-007 Page: 107 99-110