Biology of Disease

PHYSIOLOGICAL DETOXIFICATION MECHANISMS

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Blood flow

Hepatocyte

Bile canaliculi

Branch of

bile duct

Endothelial cell

Branch of

hepatic artery

Branch of

portal vein

Branch of

hepatic vein

Kupffer cell

Figure 12.2 Schematic of a portion of a liver

lobule. Blood enters at the periphery from a

branch of the hepatic portal vein and the hepatic

artery and eventually leaves at the center of

the lobule via a branch of the hepatic vein.

Close contact of the blood with the liver cells

means that these cells are the first to contact

poisons and toxins after their absorption from

the GIT and transport in the portal system.

The hepatocytes contain enzymes involved in

detoxification.

Figure 12.3 Molecular models of (A) a P-450

molecule, with a gray colored heme group

containing a central iron atom and (B) with a

bound aromatic substrate shown in dark gray.

PDB files 1PHC and 1CP4 respectively.

while the other oxygen atom is reduced to water. The NADPH supplies an
electron to complete the Phase I stage.

R-H + O 2 + NADPH + H+ R-OH + H 2 O + NADP+

The same enzyme system is able to convert unsaturated compounds to
an epoxide, which is a substrate for epoxide hydrolase that catalyzes the
conversion of the epoxide to a glycol.

The actions of these enzymes form hydroxyl groups that increase the water
solubility of the original poison or drug and also form attachment points for
the actions of Phase II enzymes. These include glucuronyl transferases of the
smooth endoplasmic reticulum membrane and sulfotransferase in the cytosol,
which use UDP-glucuronate and 3a-phosphoadenosyl 5a-phosphosulfate
(PAPS) as the respective donor substrates:

O

O

OH

HO

R 1

R 2

R 1

R 2

R 1

R 2

P-450

oxidase system

P-450

oxidase system

Epoxide

hydrolase

OH

HO

R 1

R 2