Page 278 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Liver Toxicity Chapter | 15 245

VetBooks.ir methyl groups derived from methionine, and amino acids cats, as noted above, affecting their ability to detoxify
numerous compounds including acetaminophen (Court
such as glycine and cysteine. These groups enhance water
and Greenblatt, 1997; Brown, 2001). The Gunn rat, a
solubility to allow for renal or biliary excretion of the
metabolite. Disruption of phase II reactions allows accu- mutant strain of the Wistar rat, is also deficient in UDP-
mulation of reactive phase I metabolites (Sturgill and glucuronosyltransferase enzyme. Ferrets also have less
Lambert, 1997). capability to glucuronidate (Court, 2001). Swine have
Glucuronidation is the most common phase II reaction reduced sulfate conjugation abilities (Brown, 2001). Dogs
in humans, though it is deficient in the neonate (Sturgill do not have the ability to acetylate aromatic groups,
and Lambert, 1997; Brown, 2001; Pineiro-Carrero and which may interfere with their ability to metabolize sul-
Pineiro, 2004), and, of considerable veterinary impor- fonamide antimicrobials (Brown, 2001; Trepanier, 2004).
tance, cats, which lack a functional UGA1A6 gene for Reactive metabolites of phase I metabolism can act as
glucuronyl transferase (van Beusekom et al., 2015). free radicals, substances with unpaired electrons. Free
Substrates with a molecular weight greater than 500, such radicals generate reactive oxygen species (ROS) such as
as steroid hormones, thyroxin, bilirubin, salicylates, acet- superoxide (O 2 2 ), hydroxyl radicals ( OH), and hydro-
aminophen and many other drugs are likely to undergo gen peroxide (H 2 O 2 ) through interactions with other
glucuronide conjugation. Glucuronyltransferases are molecules. Free radicals reacting with phospholipids of
microsomal enzymes that catalyze the transfer of glucuro- the plasma membrane, endoplasmic reticulum membrane
0
nide from uridine 5 -diphosphate (UDP). UDP becomes or mitochondrial membranes cause a self-propagating
depleted in overdoses of acetaminophen or other drugs chain reaction leading, eventually, to cell death (Dahm
that undergo this detoxification pathway. Products of glu- and Jones, 1996; Watkins, 1999).
curonide conjugation are excreted in bile or urine. Those Epoxides and other electrophiles are molecules with
excreted in bile sometimes undergo hydrolysis in the electron seeking properties. These form covalent bonds
intestine, leading to enterohepatic cycling. Phenobarbital with nucleophilic molecules, e.g., by binding thiol groups
is an agent that induces glucuronyltransferases. on proteins (Dahm and Jones, 1996; Watkins, 1999;
Sulfation is the primary conjugation reaction for ali- Zimmerman, 1999). Electrophiles produced by phase I
phatic alcohols and substrates with phenol groups reactions cause cell death by damage to critical proteins
(Sturgill and Lambert, 1997; Brown, 2001). These reac- such as membrane calcium transport proteins. Aflatoxin
tions are catalyzed by cytoplasmic sulfotransferases. B 1 binds to guanine residues in the DNA, leading to
Substrates for sulfate conjugation include acetaminophen, defects in protein transcription, resulting in carcinogenesis
morphine, ascorbic acid and endogenous compounds like or cell death.
chondroitin, heparin and some steroid hormones. The Aromatic amines and NSAIDs can form reactive phase II
pool of available sulfates may become saturated in drug metabolites, as mentioned previously. Glucuronides of
overdoses. aromatic amine metabolites, N-hydroxyaromatic amines,
Drugs with amine and hydrazine groups, such as sulfo- form highly electrophilic aromatic nitrenium ions that can
namides, are often conjugated to acetate (Sturgill and bind to DNA and other macromolecules, leading to urinary
Lambert, 1997; Brown, 2001). N-acetyltransferase is a bladder cancer. Several drugs, including NSAIDs, can form
cytoplasmic enzyme involved in acetylation reactions. acyl-glucuronides, which are reactive intermediates that bind
GSH and cysteine have sulfhydryl groups that readily to proteins to form adducts.
bind many phase I metabolites (Brown, 2001). GSH, a In addition to phase I and II biotransformation
free radical scavenger, prevents membrane damage from enzymes, studies suggest drug efflux from hepatocytes
reactive metabolites in spontaneous reactions or with the using hepatic transporter systems as a means of hepatic
selenium-dependent GSH peroxidases as a catalyst. xenobiotic excretion. These are called the phase III trans-
Because these enzymes are cytosolic, damaged membrane porter systems. Several transporter families that mediate
phospholipids must be released by phospholipase A2 for uptake of chemicals into liver and excretion of chemicals
detoxification. GSH is also involved in reduction and from liver into blood and/or bile have been identified.
recycling of other antioxidants such as vitamins E and C Generally, the organic anion transporting polypeptide
(Dahm and Jones, 1996). When oxidized, GSH forms a family (OATPS), organic cation transporter 1 (OCT1),
dimer that must be reduced by NADPH-dependent GSH and organic anion transporter 2 mediate uptake of a large
reductases. GSH becomes depleted in the fasting or over- number of xenobiotics from the blood to the liver.
dosed patient (Dahm and Jones, 1996; Sturgill and Conversely, multidrug resistance proteins (MDRS), multi-
Lambert, 1997; Pineiro-Carrero and Pineiro, 2004). drug resistance-associated proteins (MRPS) and breast
N-acetylcysteine is used to replenish GSH. cancer resistance protein (BCRP) mediate efflux of xeno-
Significant species differences exist in phase II biotics from liver into bile or blood (Klaassen and Slitt,
enzymes. UDP-glucuronosyltransferase is deficient in 2005). Similarly to phase I and II enzymes, these