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. 2020 Nov 2;12(11):695.
doi: 10.3390/toxins12110695.

Hepatotoxicity of Two Progoitrin-Derived Nitriles in New Zealand White Rabbits

Affiliations

Hepatotoxicity of Two Progoitrin-Derived Nitriles in New Zealand White Rabbits

Mark Grey Collett et al. Toxins (Basel). .

Abstract

Cattle occasionally develop brassica-associated liver disease (BALD) and photosensitisation when grazing turnip or swede (Brassica spp.) forage crops. The liver toxin in these brassica varieties has yet to be discovered. Progoitrin is the dominant glucosinolate in incriminated crops. Apart from goitrin, progoitrin hydrolysis yields the nitrile, 1-cyano-2-hydroxy-3-butene (CHB), and the epithionitrile, 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB). The two compounds were custom-synthesised. In a small pilot trial, New Zealand White rabbits were given either CHB or CHEB by gavage. Single doses of 0.75 mmol/kg of CHB or 0.25 mmol/kg of CHEB were subtoxic and elicited subclinical effects. Higher doses were severely hepatotoxic, causing periportal to massive hepatic necrosis associated with markedly elevated serum liver biomarkers often resulting in severe illness or death within 24 h. The possibility that one or both of these hepatotoxic nitriles causes BALD in cattle requires further investigation.

Keywords: 1-cyano-2-hydroxy-3,4-epithiobutane; 1-cyano-2-hydroxy-3-butene; BALD; brassica-associated liver disease; nitrile; progoitrin; rabbits; toxicity.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Enzyme activity (IU/L) or concentration (µmol/L) of the liver biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), glutamate dehydrogenase (GDH) and total bile acids (BA). Cases 1 and 2 received a single dose of 1 mmol/kg of 1-cyano-2-hydroxy-3-butene (CHB) and were euthanised at 24 h and 48 h postdosing (PD), respectively. Case 4 received a single dose of 3 mmol/kg and was euthanised at 8 h PD because it had a high humane endpoint score (HES). For comparison, on the left the means of the pretreatment values of all 16 rabbits plus the terminal values of the two control animals are shown.
Figure 2
Figure 2
Enzyme activity (IU/L) or concentration (µmol/L) of the liver biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), glutamate dehydrogenase (GDH) and total bile acids (BA). The results for the five rabbits given single doses of 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB) are shown, as are the size of each dose, interval until euthanasia or death (as in cases 12 and 8), and corresponding humane endpoint score (HES). For comparison, see Figure 1 for the means of the pretreatment values of all 16 rabbits plus the terminal values of the two control animals.
Figure 3
Figure 3
The liver of case 13 (dosed with 0.25 mmol/kg CHEB and euthanised at 96 h PD) was paler than normal with a prominent lobular pattern.
Figure 4
Figure 4
Photomicrographs centred on a portal tract of the liver, at the same high magnification, of (A) a normal control; (B) case 4 (3 mmol/kg CHB); and (C) case 9 (3 mmol/kg CHEB). Note the normal hepatocellular nuclear profiles in (A). In case 4 (B), there is severe periportal necrosis with hepatocellular karyorrhexis (nuclear fragmentation, arrows) and karyolysis (dissolution of the cell nucleus). In case 9 (C), hepatocytes show karyopyknosis (condensation of the chromatin and shrinkage of the nucleus, arrows) and karyolysis. Bar = 20 µm. H&E. c.v. = central vein; * = bile duct.
Figure 5
Figure 5
Photomicrographs at the same low magnification of the liver of (A) case 4 (3 mmol/kg CHB); (B) case 2 (1 mmol/kg CHB 48 h postdosing (PD); and (C) case 13 (0.25 mmol/kg CHEB 96 h PD) showing severe periportal necrosis (indicated by the straight lines). In (C), the arrows show moderate hyperplasia of bile ducts, which sometimes formed bridges between adjacent portal tracts. Bar = 200 µm. H&E. c.v. = central vein; p.t. = portal tract.
Figure 6
Figure 6
Photomicrographs of the livers of (A) case 2 (1 mmol/kg CHB at 48 h; bar = 50 µm), showing severe periportal necrosis; (B) case 8 (1 mmol/kg CHEB at 23 h; bar = 20 µm), showing karyopyknosis (solid arrow) and karyolysis (open arrows); and (C) case 11 (0.375 mmol/kg CHEB at 12 h; bar = 20 µm), showing mild mononuclear portal tract inflammatory infiltrate and apoptotic fragments (arrows). Note the karyopyknosis (condensed chromatin) in the surrounding hepatocytes, a feature typical of CHEB hepatotoxicity. H&E. c.v. = central vein; p.t. = portal tract; * = bile duct.
Figure 7
Figure 7
Photomicrographs (A) of the liver of case 9 (3 mmol/kg CHEB at 2.5 h PD; bar = 20 µm) showing lysed hepatocytes (open arrows) sometimes containing heterophils (emperipolesis, solid arrow); (B) and (C) kidney of case 14 (1 mmol/kg CHB combined with 0.25 mmol/kg CHEB at 96 h PD) showing necrosis of pars recta tubules, indicated by the circle in (B) and the arrows in (C). Bar in (B) = 50 µm and in (C) = 20 µm. H&E.

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