Page 1089 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Ochratoxins and Citrinin Chapter | 72 1021

VetBooks.ir alpha in the urine. Its presence in the urine can be studies, LC-MS/MS has been used to determine the con-
centrations of citrinin and HO-CIT in urine (Ali et al.,
explained by reabsorption from the intestine. A similar
2015; Huybrechts et al., 2015; Fo ¨llmann et al., 2016).
mechanism of intestinal reabsorption of ochratoxin alpha
has been suggested to occur in ruminant calves
(Sreemannarayana et al., 1988). In sheep, Ho ¨hler et al.
MECHANISM OF ACTION
(1999) demonstrated that OTA hydrolysis in the gastroin-
testinal tract was substantially less than previously Both OTA and citrinin are well-known nephrotoxicants.
described, especially if OTA was ingested in combination In addition to nephrotoxicity, OTA is known to exert
with concentrate-rich diets. For further details on metabo- neurotoxic, immunotoxic, teratogenic and carcinogenic
lism of OTA, readers are referred to Wu et al. (2012) and effects in mammalian species. OTA also disrupts blood
Malir et al. (2013). coagulation and glucose metabolism. In general, the
OTA and its metabolites excrete in the urine and feces mechanisms associated with OTA toxicity include inhibi-
in all species (Ho ¨hler et al., 1999; Ringot et al., 2006; tion of protein synthesis, ROS formation, lipid peroxida-
Coronel et al., 2011; Klapec et al., 2012). OTA also tion, disturbance of calcium homeostasis and impairment
passes in the milk in animal species (such as rats and rab- of mitochondrial oxidation reactions. A brief description
bits) and humans (Munoz et al., 2014), but very little is of the mechanisms involved in common toxic effects is
excreted in cows’ milk because of its metabolism by the given below.
ruminal microflora (Breitholtz-Emanuelsson et al., 1993;
Signorini et al., 2012). This route is of importance Nephrotoxicity
because the milk is consumed by the offspring.
Subsequent to its urinary excretion, OTA is reabsorbed in Both OTA and citrinin produce nephrotoxicity involving
all nephron segments. Excretion of OTA can be influ- multiple mechanisms. At high doses, OTA affects both
enced by the route of administration, the dose and the renal function and morphology, as indicated by increased
gender, age and weight of the animal (Vettorazzi et al., weight, urine volume, blood urea nitrogen, urinary glu-
2009, 2014). Excretion of OTA is also impacted by the cose, and proteinuria. The last two findings indicate that
extent of enterohepatic circulation and binding to serum the site of reabsorption (i.e., the proximal convoluted
albumin and other macromolecules (Galtier et al., 1980; tubules) is damaged. OTA specifically causes defect of
Hult and Fuchs, 1986). The association constant for the the organic anion transport mechanism located on the
4
binding of OTA to serum albumin is 7.1 3 10 per mol brush border of the proximal convoluted tubules and
4
4
for pigs, 5.1 3 10 per mol for chickens and 4.0 3 10 per basolateral membranes. OTA also adversely affects the
mol for rats (Galtier et al., 1981). organic ion transport system by which OTA enters the
Placental transfer of OTA in mammalian species like proximal tubular cells. The middle (S2) and terminal (S3)
mice, rat and swine is well known. However, in ruminants segments of the proximal tubule of the isolated nephron
the placental transfer of OTA is very little. After intrave- are the most sensitive to the toxic effects of OTA, as evi-
nous administration of a high dose of OTA (1 mg/kg body denced by marked decreases in cellular and mitochondrial
weight) to pregnant ewes, Munro et al. (1973) did not ATP contents.
detect OTA in the amniotic fluid and fetal tissue levels Studies suggest that both OTA and citrinin cause mito-
were 400 1000 times lower than in the maternal blood. chondrial dysfunction in renal and hepatic tissues (Aleo
The exact mechanism involved in placental transfer of et al., 1991; Chagas et al., 1995). OTA toxicity is associ-
OTA is yet to be elucidated. OTA can be present in eggs ated with inhibition of both protein and RNA synthesis
due to its biliary excretion if the laying hens are exposed to (Dirheimer and Creppy, 1991). OTA is known to interfere
this mycotoxin at high doses (Armorini et al., 2015). with the charging of tRNA with amino acids. OTA treat-
By now, it is clear from several animal studies that OTA ment can increase oxidative stress in peripheral organs.
has a high degree of bioavailability, a low plasma clearance Administration of OTA to rats (1 mg/kg) resulted in a
rate and a long tissue half-life. Because of the differences in 22% decrease in α-tocopherol plasma levels and a five-
animal physiology, wide variations are seen in the toxicoki- fold increase in the expression of the oxidative stress
netic patterns of OTA. For further details on biotransforma- responsive protein heme oxygenase-1, specifically in
tion, toxicokinetics, and toxicodynamics of OTA, readers the kidney (Gautier et al., 2001). Cell death occurs by
are referred to recent publications elsewhere (Ringot et al., apoptosis (Ramyaa and Padma, 2013).
2006; Vettorazzi et al., 2014; Gupta et al., 2017).
Toxicokinetic data of citrinin in animals are scarce due
Neurotoxicity
to lack of a validated method to determine the concentra-
tions of citrinin and its major metabolite dihydrocitrinone Evidence strongly suggests that OTA affects selected
(HO-CIT) in body fluids and tissues. In recent human structures of the brain and it has the potential for