Free accessResearch articleFirst published online 2010-9
Developing and Characterizing a Mouse Model of Hepatotoxicity Using Oral Pyrrolizidine Alkaloid (Monocrotaline) Administration,with Potentiation of the Liver Injury by Co-administration of LPS
Oral administration of xenobiotics is preferable for research in In Vivo models because it mimics the real life situation of human subjects. Therefore, oral (po) monocrotaline (MCT) (a common contaminant of dietary supplements)/intraperitoneal (ip) lipopolysaccharides (LPS)-induced liver injury possibly imitates idiosyncratic hepatotoxicity in humans. Cytokines, for example interleukin-1β (IL-1β) and transforming growth factor beta (TGF-β) are known to play a role in the development of toxicity and repair processes, respectively. The purpose of this study was to develop and characterize a model of po MCT/ip LPS hepatotoxicity which may elucidate the mechanisms of injury. ND4 male mice were given MCT (200 mg/kg) followed 4 h later by LPS (6 mg/kg). Blood samples were drawn for plasma chemistry and IL-1β. Animals were euthanized and livers were harvested at different time points. We have shown that MCT/LPS cotreatment results in significant elevation of plasma alanine aminotransferase (ALT), CRP, IL-1β and TGF-β. Histopathological evaluation revealed diffuse degenerative injury. In summary, we have established a reproducible in vivo model of hepatotoxicity by po MCT/ip LPS cotreatment that may closely mimic real life idiosyncratic hepatotoxicity.
MingattoFE, DortaDJ, dos SantosAB, CarvalhoI, da SilvaCH, da SilvaVB, UyemuraSA, dos SantosAC, CurtiC. (2007) Dehydromonocrotaline inhibits mitochondrial complex I. A potential mechanism accounting for hepatotoxicity of monocrotaline. Toxicon, 50, 724–730;
3.
MaddoxJF, AmuzieCJ, LiM, NewportSW, SparkenbaughE, CuffCF, PestkaJJ, CantorGH, RothRA, GaneyPE. (2010) Bacterial- and viral-induced inflammation increases sensitivity to acetaminophen hepatotoxicity. Journal of Toxicology and Environmental Health, 73, 58–73;
CoppleBL, RondelliCM, MaddoxJF, HoglenNC, GaneyPE, RothRA. (2004) Modes of cell death in rat liver after monocrotaline exposure. Toxicological Sciences, 77, 172–182;
7.
ImaedaA., WatanabeA, SohailMA, MahmoodS, MohamadnejadM, SutterwalaFS, FlavellR., MehalWZ. (2009) Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. Journal of Clinical Investigation, 119, 305–314; TilgH. (1993) The role of cytokines in the pathophysiology of chronic liver diseases. International Journal of Clinical Laboratory Research, 23, 179–185.
8.
CalabroP, ChangDW, WillersonJT, YehET. (2005) Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. Jounal of American College of Cardiology, 46, 1112–1113.
9.
SasakiK, FujitaI, HamasakiY, MiyazakiS. (2002) Differentiating between bacterial and viral infection by measuring both C-reactive protein and 2′-5′-oligoadenylate synthetase as inflammatory markers. Journal of Infection and Chemotherapy, 8, 76–80.
10.
TuratoC, CalabreseF, BiasioloA, QuartaS, RuvolettoM, TonoN, PaccagnellaD, FassinaG, MerkelC, HarrisonTJ, GattaA, PontissoP. (2010) SERPINB3 modulates TGF-beta expression in chronic liver disease. Laboratory Investigation, doi:10.1038/labinvest.2010.55; published online 8 March 2010;
11.
YeeSB, HanumegowdaUM, CoppleBL, ShibuyaM, GaneyPE, RothRA. (2003) Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysaccharide coexposure. Toxicological Sciences, 74, 203–14;
12.
SunH, KoikeT, IchikawaT, HatakeyamaK, ShiomiM, ZhangB, KitajimaS, MorimotoM, WatanabeT, AsadaY, ChenYE, FanJ. (2005) C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance. American Journal of Pathology, 167, 1139–1148.
13.
Galve-deRB, WiktorowiczK, KushnerI, DayerJM. (1993) C-reactive protein increases production of IL-1 alpha, IL-1 beta, and TNF-alpha, and expression of mRNA by human alveolar macrophages. Journal of Leukocyte Biology, 53, 439–445;
14.
Du ClosTW. (2000) Function of C-reactive protein. Annals of Medicine, 3, 274–278;
15.
FreemanDJ, NorrieJ, CaslakeMJ, GawA, FordI, LoweGD, O'ReillyDS, PackardCJ, SattarN. (2002) C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes, 51, 1596–1600;
16.
OrucN, OzutemizO, YuceG, AkarcaUS, ErsozG, GunsarF, BaturY. (2009) Serum procalcitonin and CRP levels in non-alcoholic fatty liver disease: a case control study. BMC. Gastroenterology, 9, 16–20;
17.
AronsonD, BarthaP, ZinderO, KernerA, ShitmanE, MarkiewiczW, BrookGJ, LevyY. (2004) Association between fasting glucose and C-reactive protein in middle-aged subjects. Diabetic Medicine, 21, 39–44;
18.
JamesLP, MayeuxPR, HinsonJA. (2003) Acetaminophen-induced hepatotoxicity. Drug Metabolism and Disposition, 31, 1499–1506.
19.
NystromT. (2007) C-reactive protein: a marker or a player?Clinical Science (London), 113, 79–81;
20.
KanzlerS, LohseAW, KeilA, HenningerJ, DienesHP, SchirmacherP, Rose-JohnS, zum BuschenfeldeKH, BlessingM. (1999) TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. American Journal of Physiology, 276, G1059-G1068.
RomanoM, GuagnanoMT, PaciniG, VigneriS, FalcoA, MarinopiccoliM, ManigrassoMR, BasiliS, DaviG. (2003) Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women. Journal of Clinical Endocrinology and Metabolism, 88, 5321–5326;
26.
TaylorAW, KuNO, MortensenRF. (1990) Regulation of cytokine-induced human C-reactive protein production by transforming growth factor-beta. The Journal of Immunology, 145, 2507–2513;
27.
McGeeDW, BeagleyKW, AicherWK, McGheeJR. (1993) Transforming growth factor-beta and IL-1 beta act in synergy to enhance IL-6 secretion by the intestinal epithelial cell line, IEC-6. The Journal of Immunology, 151, 970–978.
