etabolitesExcretion and Elimination of Toxicants and their Metabolites
The first topic that was covered by this chapter was the excretion of wastes
by the Renal system. The first step that occurs in the kidney deals with the
nephron, which is the functional unit of the kidney. In the glomerulus the
formation of urine begins with the passive filtration of plasma through the
pores that are found in the glomerulus. The plasma is forced through these pores
by hydrostatic pressure. The only things that determines if a molecule will pass
through the pores of the glomerulus is it’s molecular weight. The lower the
molecular weight, the easier it will pass through the pores. Another
determining factor will be if a molecule is bound to a large molecule. If this
is true then passage through the pores will be hindered by the size of the
Reabsorbtion of the many ions, minerals and other nutrients that escaped in
the glomerular filtrate will need to be recovered.. Reabsorbtion begins in the
tubules of the nephron. Anywhere from 65% to 90% of reabsorbtion occurs in
these structures. Active reabsortion is used to recapture glucose, proteins,
amino acids and other nutrients. Water and chloride ions are passively
reabsorbed by the establishment of osmotic and electrochemical gradients. Both
the Loop of Henley and collecting duct are used to establish these osmolar
gradients. The tubule has a brush border that will absorb proteins and
polypeptides through pinocytosis. These molecules are sometimes catabolised and
converted into amino acids. and returned to the blood. Sometimes the
accumulation of these proteins can lead to renal toxicity
A second process that occurs in the tubules is tubular secretion. This is
another mechanism used to excrete solutes. Secretion may be either passive or
active. Secretions include organic bases, which occur in the pars recta of the
proximal tubule. Secretions of weak bases and two weak acids occur passively.
Other mechanisms involves the use of a mechanism that is called ion trapping. At
a certain pH the compounds are more ionized. Outside of the tubule these
compounds are non-ionized and are lipophilic. Thus they are able to diffuse
across the membranes of the tubule. Once inside, the pH of the tubule will
ionize them and render then unable to pass across the cell membranes.
The removal of xenobiotics is dependant on many factors. First is the
polarity of the xenobiotic. Polar compounds are soluble in the plasma water are
more easily removed by the kidneys through the use of glomerular filtration. The
faster the rate of glomerular filtration , the faster the polar xenobiotics are
eliminated from the body. Other factors that affect the rate of elimination
include: dose of the xenobiotic, the rate pf absorbtion, and the ability to bind
to proteins as well as the polarity of the compound.
In comparison lipophilic compounds will cross the cell membrane with more
ease. Due to their lipohpillic properties they will follow the their
concentration gradient across the membrane of the tubules and are ,therefore,
easily retained by the body. If a lipophilic compound is metabolized to a more
polar state then it is more easily metabolized. Another important factor that
will determine excretion by the kidneys will be the pH of the environment. Those
compounds that are effected by pH will have both an ionized and nonionic form.
When in their nonionized form it will rebsorbed by the tubules and kept their
because of their change to an ionized form.
The liver is the second most important organ that is involved in the removal
of wastes from the body. The primary methood of excretion involvrd the Hepatic
cells of the liver. Both passive and active modes of transport are used.
Bile is excreted by the hepatic cells. It is a concentration of amphipatic
compounds that will aid in the transport of lipids from the small intestine.
Before reaching the small intestine, via the common bile duct, it will be stored
and concentrated in the gall bladder. The bile will then be reabsorbed by a
process known as enterohepatic circulation.
The more lipophilic or nonionized a compound is, the more readily it will be
absorbed. Solubility is another factor that will determine absorbance. The rapid
absorbance of these compounds does not mean that they will not be readily
excreted. Some compounds are readily excreted after absorbtion.
Most toxic xenobiotics are very lipophilic. This means that they will be
easily ablorbed and dispursed among the tissue. Their liphilic characterizations
also means that there excretion in either the urine or bile will be in very
small amounts, unless they are metabolized ito more polar compounds.
One of the methods used to dispose toxic lipophilics is by degradation of the
large compounds into small polar fragments thatcan be eliminated through the
urine or bile. Oxidative metabolism of toxic cyclic and polycyclic hydrocarbons
is done with the introduction of a hyroxyl group into the ring structure. The
excretion of halogenated hydrocarbons is extremely difficult. Their accumulation
in the body occurs in both adipose tissue and lipid layers of the skin. They
will stay there for the duration of theanimals life time.
The molecular weight of a compound will determine if the compound will be
excreted in the urine or feces. Any elimination of a xenobiotic will be done in
association with the excretion of another compound that is normally eliminated
by the body. Most gaseous and volatile xenobiotics are eliminated through the
lungs. The rate of ecretion is based on how soluble the compond is in the blood,
the rate of volume of respiration, and the rateof blood flow to the lungs.
Asecond method used is the alveolobronchilar transport mechanism. Which will
involve the use of the mucociliary bronchotracheal escalator that will end with
the material being swallowed and passed out of th body.
Sex linked elimination is restricted to the female.The milk excreted by the
mother will contain the largest number of possible xenobiotics.The elimination
of the xenobiotic is dependant on the half-lifeof the compound. Most of the
compounds that are excreted are low in dosage and therefore are not lethal.
Chronic exposure can be toxic to the nursing young. The type of materials that
are excreted are lipophilic because they are not excreted by the other major
pathways. In eggs the type of compound eliminated are also limpohpilic in
nature. Fetuses are mostly effected by lipophilic compounds that are ablr to
pass the placental barrier. There are cases of fatal exposure of xenobiotics to
the fetus through the mother.