Page 277 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

244 SECTION | II Organ Toxicity

VetBooks.ir copper storage disease has been reported in cats and fer- microsomal enzymes, are the most common players of
Cytochrome P450 enzymes, a major group of the
rets (Huynh and Laloi, 2013). Sheep and some other spe-
phase I oxidation. All P450 enzymes contain a heme iron
cies are susceptible to a form of copper storage disease
with an acute presentation. Other causes of hepatocellular center and when complexed within carbon monoxide,
damage in sheep cause copper release and oxidative absorb light at a wavelength of 450 nm. These enzymes
damage to surrounding hepatic parenchyma as well as were first discovered in an unknown pigment thus named
erythrocytes. cytochrome P450: P for pigment and 450 for the wave-
The ability to excrete a toxicant into the bile duct will length of absorbed light. Liver P450 enzymes involved in
usually result in clearance by excretion in feces or urine. xenobiotic biotransformation belong to three main P450
However, certain lipophilic compounds such as methyl- gene families, CYP1, CYP2, and CYP3. More than 36
mercury and diclofenac can be reabsorbed from the intes- cytochrome P450 isoenzymes have been identified in ani-
tinal lumen back into the portal circulation, a process mals (Dahm and Jones, 1996; Watkins, 1999; Jaeschke,
known as enterohepatic cycling. This will lead to pro- 2008). P450s can be induced or inhibited by drugs such
longed biological half-life and can increase the toxicity of as phenobarbital and cimetidine, respectively. Oxidation
the compound (Jaeschke, 2008). is the major phase I reaction, and the most important
enzyme system for oxidative reactions are the cytochrome
P450 (Gu and Manautou, 2012). Important substrates
Bioactivation and Metabolism
include steroid hormones, bile acids, fat soluble vitamins,
One of the major functions of the liver is the elimination and more than 90% of drugs (Brown, 2001; Gu and
of both endogenous and exogenous compounds. Some Manautou, 2012). Oxidative reactions can produce highly
xenobiotic agents absorbed by the small intestine are reactive epoxides, which are usually detoxified rapidly by
highly lipophilic. Renal excretion is the primary mecha- phase II conjugation or hydrolysis by microsomal epoxide
nism of removal for many xenobiotics, but renal excretion hydrolase enzymes (Watkins, 1999; Pineiro-Carrero and
of lipophilic compounds, which are frequently protein Pineiro, 2004). If an individual is exposed to the xenobi-
bound in the circulation, is poor (Dahm and Jones, 1996; otic in high enough doses that these mechanisms are over-
Sturgill and Lambert, 1997; Watkins, 1999). Therefore, in whelmed, reactive phase I metabolites produce injury.
order for these xenobiotics to be eliminated, biotransfor- Noncytochrome P450 enzymes are also involved in
mation needs to occur in the liver first to increase their oxidative reactions. One such enzyme is alcohol dehydro-
water solubility. genase, a cytosolic enzyme, whose substrates include vita-
Hepatocytes contain phase I enzymes, which expose min A, ethanol, and ethylene glycol. Others such enzymes
or introduce functional groups ( OH, NH 2 , SH or include aldehyde dehydrogenase, aldehyde oxidase, xan-
COOH) and generate reactive electrophilic metabolites. thine oxidase, monoamine oxidase, diamine oxidase, per-
Hepatocytes also have a wide variety of phase II enzymes oxidase, and flavin-monooxygenases (Jaeschke, 2008).
that enhance the hydrophilicity by a conjugation reaction, Examples of phase I reduction reactions include reduc-
which adds a polar group to promote excretion. The func- tion of nitro compounds to amines, and dehalogenation of
tional groups exposed or introduced by the phase I volatile anesthetics. Phase I hydrolysis reactions are
enzymes often become the site of action for the phase II required for metabolism of compounds with amide bonds
reactions. Though these reactions function to detoxify or ester linkages, as in the conversion of aspirin to salicy-
compounds, if there is a mismatch between phase I and II late (Brown, 2001). Carboxylesterase, alkaline phospha-
reactions, there is potential for accumulation of toxic tase, peptidase, and epoxide hydrolase are involved in
phase I metabolites (Zimmerman, 1999; Jaeschke, 2008). phase I hydrolysis reactions (Jaeschke, 2008).
Phase I reactions, ubiquitous in mammals, involve oxi- Most phase II enzymes are cytosolic, but others are
dation, reduction and hydrolysis, and sometimes produce mitochondrial or microsomal. Phase II enzymes are pre-
biologically active metabolites (Brown, 2001). Phase I dominantly involved in conjugating xenobiotics at the
enzymes are predominantly located in zone 3, as men- functional groups of the parent compound or the phase I
tioned previously. Many of these phase I enzymes are metabolites. Unlike the phase I metabolites, phase II
present in the smooth endoplasmic reticulum of the hepa- metabolites are rarely reactive, with some exceptions such
tocyte. When liver tissue is homogenized mechanically in as the glucuronide product of some nonsteroidal antiin-
a laboratory, the endoplasmic reticulum breaks down into flammatory drugs and aromatic amines (Jaeschke, 2008),
small vesicles known as microsomes and can be retrieved which will be discussed later.
by differential centrifugation. Thus these enzymes are Phase II enzymes conjugate a polar group to a
often referred to as microsomal enzymes. As a rule, hydroxyl-, carboxyl-, amino- or sulfhydryl-group on the
microsomal enzymes require oxygen and NADPH to substrate. These polar molecules include glucuronic acid,
function (Dahm and Jones, 1996; Brown, 2001). sulfate derived from sulfuric acid ester, acetate, GSH,