Enrico Tiepolo
The Liver and its detoxifying role
The liver has an emunctory function, as it eliminates some substances in the bile and helps the kidney
to eliminate other substances. This action is not selective on “toxic” substances.
Life is generally based on the continuous turnover of the components of the organism itself; so, anything
that enters the organism, but also all compounds synthesized by the organism itself, must sooner or later
be destroyed and/or eliminated.
The kidney easily eliminates hydrophilic substances that, once filtered, cannot passively diffuse across
the tubular epithelium and are lost in the urine; lipophilic substances instead are not eliminated easily:
they can diffuse back when 99% of the filtered fluid is reabsorbed. So, the rationale (the philosophy)
of liver activity is to make any lipophilic substance more hydrophilic; as well as degrading
proteins and big polymers.
It is now clear that the liver is concerned with metabolizing and degrading big molecules like proteins
or cholesterol, eliminating what it can eliminate and making whatever is not easily eliminated by the
kidney more hydrophilic so that the kidney will more easily eliminate it. This detoxyfing role follows a
specific mechanism made of 2 phases. During the first phase, normal-size molecules and small molecules
are made hydrophilic through functionalization while big molecules are made amphipathic; then during
the second phase “conjugation” happens, which is not always needed. Let’s analyze more deeply the key
words here:
• functionalization, i.e. introduction of functional (reactive) groups in the lipophilic molecule
(chemical group that can react with something, for example a hydroxy group, or a sulfur,
aldehyde or COOH): such groups (e.g., -OH) are generally polar and increase hydrophilicity.
The product of this functionalization is now ready to be excreted in the urine (after being
released back into the circulation and filtered by the kidney).
• conjugation with a hydro-soluble molecule (e.g., glucuronate or a glicine residue), making the
molecule at least partly polar by the addition of a polar molecule. Not always the conjugation is
needed, sometimes functional groups are enough to make a molecule more hydrophilic, helping
with renal clearance or directing them to the bile. It depends on the substance: e.g. bilirubin,
when conjugated, is very much more easily excreted.
• Generation of amphipathic (both hydrophilic and lipophilic) molecules, even bigger than the
original, is a mechanism particularly suitable for the secretion in the bile (transport mechanisms
in the bile preferentially transport big amphipathic molecules).
However, conjugated substances that end up in the bile, which possess an ester bond between the initial
molecule and the glucuronic acid or glycine, are easily targeted by the esterase-enzymatic activity
of bacteria in the gut (cleave the ester bond) making the substance lipophilic again and prone to be
reabsorbed in the portal circulation. This is referred to as entero-hepatic recycling, which is useful,
for example, in the recycling of bile salts and cholesterol, but becomes a problem in the metabolism of
some lipophilic drugs that will be reabsorbed exploiting this mechanism, so it will be necessary to break
them down by taking out some functional groups that accounts for their effect, neutralizing them this
way, or, another way of degrading them would be through the kidney.
The liver and the kidney are therefore organized to eliminate and degrade everything, since everything
that is in the living organism should be sooner or later turned over, except the substances that are
absolutely necessary (the substrates: glucose, amino acids, lipids). In a similar way autophagy keeps the
cells “young”, by continuously turning them over.
108 Body At Work II
The Liver and its detoxifying role
The liver has an emunctory function, as it eliminates some substances in the bile and helps the kidney
to eliminate other substances. This action is not selective on “toxic” substances.
Life is generally based on the continuous turnover of the components of the organism itself; so, anything
that enters the organism, but also all compounds synthesized by the organism itself, must sooner or later
be destroyed and/or eliminated.
The kidney easily eliminates hydrophilic substances that, once filtered, cannot passively diffuse across
the tubular epithelium and are lost in the urine; lipophilic substances instead are not eliminated easily:
they can diffuse back when 99% of the filtered fluid is reabsorbed. So, the rationale (the philosophy)
of liver activity is to make any lipophilic substance more hydrophilic; as well as degrading
proteins and big polymers.
It is now clear that the liver is concerned with metabolizing and degrading big molecules like proteins
or cholesterol, eliminating what it can eliminate and making whatever is not easily eliminated by the
kidney more hydrophilic so that the kidney will more easily eliminate it. This detoxyfing role follows a
specific mechanism made of 2 phases. During the first phase, normal-size molecules and small molecules
are made hydrophilic through functionalization while big molecules are made amphipathic; then during
the second phase “conjugation” happens, which is not always needed. Let’s analyze more deeply the key
words here:
• functionalization, i.e. introduction of functional (reactive) groups in the lipophilic molecule
(chemical group that can react with something, for example a hydroxy group, or a sulfur,
aldehyde or COOH): such groups (e.g., -OH) are generally polar and increase hydrophilicity.
The product of this functionalization is now ready to be excreted in the urine (after being
released back into the circulation and filtered by the kidney).
• conjugation with a hydro-soluble molecule (e.g., glucuronate or a glicine residue), making the
molecule at least partly polar by the addition of a polar molecule. Not always the conjugation is
needed, sometimes functional groups are enough to make a molecule more hydrophilic, helping
with renal clearance or directing them to the bile. It depends on the substance: e.g. bilirubin,
when conjugated, is very much more easily excreted.
• Generation of amphipathic (both hydrophilic and lipophilic) molecules, even bigger than the
original, is a mechanism particularly suitable for the secretion in the bile (transport mechanisms
in the bile preferentially transport big amphipathic molecules).
However, conjugated substances that end up in the bile, which possess an ester bond between the initial
molecule and the glucuronic acid or glycine, are easily targeted by the esterase-enzymatic activity
of bacteria in the gut (cleave the ester bond) making the substance lipophilic again and prone to be
reabsorbed in the portal circulation. This is referred to as entero-hepatic recycling, which is useful,
for example, in the recycling of bile salts and cholesterol, but becomes a problem in the metabolism of
some lipophilic drugs that will be reabsorbed exploiting this mechanism, so it will be necessary to break
them down by taking out some functional groups that accounts for their effect, neutralizing them this
way, or, another way of degrading them would be through the kidney.
The liver and the kidney are therefore organized to eliminate and degrade everything, since everything
that is in the living organism should be sooner or later turned over, except the substances that are
absolutely necessary (the substrates: glucose, amino acids, lipids). In a similar way autophagy keeps the
cells “young”, by continuously turning them over.
108 Body At Work II
