Page 590 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Herbicides Chapter | 44 555

VetBooks.ir by paraquat, which indicates the involvement of MATE-1 pigs. In rats, diquat monopyridone has been identified in
the feces, at approximately 5% of an oral dose, whereas
(multidrug and toxin extrusion) in paraquat renal transport
diquat dipyridone has been detected in urine. These
(Winter et al., 2011). It is clear that paraquat can enter a
renal cell via OCT2 and, to a lesser extent, OCT1 and results indicate that diquat is probably metabolized by GI
then be transported out of the cell by MATE-1. However, bacteria (JMPR, 1993).
whether MATE-2k can transport paraquat is not known Ureas and thioureas such as diuron are readily
(Chan et al., 1998; Lock and Wilks, 2010; Winter et al., absorbed through the GI tract in rats and dogs and are
2011). A schematic representation of the proposed trans- mainly metabolized by dealkalization of the urea methyl
port systems for paraquat across renal tubular cells is groups. The predominant metabolite of diuron in urine is
shown in Figs. 44.1 and 44.2. N-(3,4-dichlorophenyl)-urea. Diuron is partially excreted
Unlike paraquat, diquat does not accumulate in the unchanged in feces and urine. The storage of diuron does
lungs; however, it is observed in liver, kidney, plasma not occur in tissues (Boehme and Ernst, 1965; Hodge
and adrenal gland. Diquat does not enter the brain (Rose et al., 1967; Liu, 2010).
et al., 1976). Following oral administration, 90% 98% of Organophosphorus herbicides such as glyphosate and
the dose is eliminated via the urine (Daniel and Gage, glufosinate are poorly absorbed both orally and via the
1966). Metabolism studies indicate some unidentified dermal route. There is rapid elimination, and these are not
metabolites of diquat in the urine of rabbits and guinea biotransformed and do not accumulate in tissues. More
than 70% of an orally administered dose of glyphosate is
Cimetidine
quinine H + 0 Na + rapidly eliminated through feces and 20% through urine.
PQ +2 OCT1 0 2H + The main metabolite of glyphosate is aminomethylpho-
PQ +2 sphonic acid (AMPA); AMPA is of no greater toxicologi-
PQ +2 +2
P-glycoprotein PQ cal concern than its parent compound (JMPR, 2004).
PQ +2 OCT2 The proton class of oxidase inhibitor herbicides is
pH pH pH either not readily absorbed or is rapidly degraded by
7.4 7.2 6.7 metabolism and/or excreted. In mammals, there are
Basolateral Apical remarkable species differences in the levels of porphyrin
membrane membrane
accumulation resulting from exposure to Protox inhibitors.
FIGURE 44.1 Schematic representation of the proposed transport sys- There is no bioaccumulation risk to animals. The carbox-
tems for paraquat across renal tubular cells. The transporters are OCT1 yester group of the triazolinone herbicide carfentrazone
and OCT2 at the basolateral membrane and P-glycoprotein and the ethyl is initially metabolized to a carboxylic acid group.
1
cation/H exchange system at the brush border membrane. Reproduced Other metabolites identified in rats and lactating goats
with permission from Chan, B.S.H., Lazzaro, V.A., Seale, J.P., Duggin, include hydroxymethylpropionic acid and cinnamic acid
G.G., 1998. The renal excretory mechanisms and the role of organic
cations in modulating the renal handling of paraquat. Pharmacol. Ther. derivatives, which are further metabolized to yield a
79, 193 203. benzoic acid derivative (Aizawa and Brown, 1999).

Urine
H + (Bile) H + MATE1
MATE1
Renal proximal tubules (hepatocytes) AGM 2+ AGM 2+ AGM 2+ AGM 2+

2+ OCT2 (OCT1) Blood OCT2 (OCT1) 2+
AGM AGM
FIGURE 44.2 Proposed mechanism of agmatine transport in tissues (i.e., kidney and liver) widely recognized to express OCT1, OCT2 and MATE-1.
Organic cation transporter (OCT) 1 and 2 mediate the facilitated influx transport of organic cations at the basolateral membrane of hepatocytes and
1
renal proximal tubule cells, respectively. The multidrug and toxic compound extrusion (MATE) transporter 1, an H /cation antiporter, is critical in the
efflux elimination of various organic cations from the brush border and canalicular membrane of the kidney and liver, respectively. (Descriptions in
parentheses refer to equivalent structures in the liver.) Reproduced with permission from Winter, T.N., Elmquist, W.F., Fairbanks, C.A., 2011. OCT2
and MATE1 provide bidirectional agmatine transport. Mol. Pharm. 8, 133 142.