MUDr. Dana Maňasková

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Hepatotoxiny

Hepatotxické látky


Acrolein

  • Cytotoxicity in hepatocytes involves
    • Endoplasmic reticulum stress
    • mitochondrial dysfunction
    • Oxidative stress [4]

Aflatoxiny


Aflatoxin B(1) (AFB)

  • Secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus
    • Peanuts, pistachios, corn, and rice
  • Human hepatocellular carcinoma
  • Protektivní efekt:
    • Induction of detoxification enzymes such as certain glutathione-S-transferases that are regulated through the Keap1-Nrf2-ARE signaling pathway [2]
      • Dithiolthione drug
      • Oltipraz
      • Suforaphane (SFN) [2]
        • Spíše u krys, ne u lidí [2]
        • Repression of human hepatic CYP3A4 expression [3]
    • Decrease in the rate of activation of AFB to AFBO [2]
      • Apiaceous vegetables
        • Potent inhibitors of human CYP1A2
          • Reduced hCYP1A2-mediated mutagenicity of AFB [2]
    • Snížená absorpce
      • Chlorophyllin, to tightly bind to and reduce the bioavailability of aflatoxins [3]
        • Significantly reduce genotoxic AFB biomarkers in humans
          • Reducing the incidence of AFB-induced liver cancer [3]
    • Gene expression of enzymes potentially involved in nucleotide excision repair of AFB-DNA adducts [3]

Alcohol

  • Metabolism of ethanol
    • Enhanced lipid peroxidation during
      • Hepatitis
        • Cirrhosis

Animal models

  • A single dose of ethanol 1 ml/kg induces fatty degeneration in mice [4]
  • Administration of 40 % (v/v) ethanol 2 ml/100g/day p.o for 21 days produces fatty liver [4]
  • Country made liquor 3ml/100g/day p.o for 21 days produces liposis [4]

Antibiotika

  • Pouze některá - nemám ještě dohledaná

Carbon tetrachloride (CCL4)

  • Trichloromethyl free radical (CCl3-)
    • Metabolic formation, highly reactive
    • Enhanced by induction of hepatic microsomal enzyme systems [4]
  • Attacks the polyunsaturated fatty acids
    • Membrane of the endoplasmic reticulum
    • Initiates a chain reaction [4]
  • Biphasic injury:
  • 1st x centrilobular region with greatest microsomal enzyme activity
  • 1st x highly localised x in the endoplasmic reticulum by CCl3- itself
    • Loss of cytocrome p450 leading
    • Decrease in protein synthesis
    • Accumulation of TG - fatty liver [4]
  • 2nd x water and electrolyte balance of hepatocytes - cascade of lipid peroxidation
    • Abnormal increase in liver enzymes in plasma
    • Impairing mitochondrial functions
    • Hepatocellular necrosis [4]

Animal models

  • Used for predicting the mode of action of the hepatoprotective agent [4]
  • ACUTE HEPATIC DAMAGE:
    • By p.o./s.c. CCl4 (1.25 ml/kg) as 50 % V/V solution in liquid paraffin / olive oil [4]
    • Biochemical tests max change after 24h [4]
      • Ischemia
      • Hydropic degeneration
      • Central necrosis [4]
  • CHRONIC REVERSIBLE HEPATIC DAMAGE:
    • CCl4 (1ml/kg s.c) 2x tý po 8 tý [4]
  • CHRONIC, IRREVERSIBLE HEPATIC DAMAGE:
    • CCl4 (1ml/kg s.c) 2x tý po 12 tý [4]

Chloroform

  • Extensive central necrosis
  • Fatty metamorphosis
  • Hepatic cell degeneration and necrosis
  • 1h of inhalation / s.c. 0,4-0,5 ml/kg [4]

D-Galactosamine

  • 800 mg /kg i.p induces acute hepatotoxicity after 48h [4]
-diffused necrosis and steatosis [4]

Chemoterapie


Microbes

  • Některé druhy a jejich metabolity - nemám ještě dohledané

Nikl

  • Chronic nickel toxicities in peripheral tissues like
    • Liver, lungs, and kidneys [1]
  • Nickel-induced generation of reactive oxygen species and increased lipid peroxidation in various metabolically active tissues in humans and animals
  • Possible role of vitamin c as a protective antioxidant [1]

Paracetamol

  • Acute hepatotoxicity depending upon its dosage
    • 800 mg/kg i.p. [4]
      • Centrilobular necrosis without steatosis
    • 3 g/kg p.o stimulates acute hepatic damage [4]
  • Small doses
    • Eliminated by conjugation followed by excretion [4]
  • Higher doses
    • Conjugation enzymes are saturated
    • Alternative metabolic pathway by cytochrome P450 enzyme
      • Hydroxylamine derivative
        • Reactive electrophillic agent
        • Reacts non-enzymatically with glutathione and detoxifies [4]
  • Even higher doses
    • Hepatic reserves of glutathione depletes
    • Hydroxylamine reacts with macromolecules
      • Disrupts their structure and function [4]
      • Extensive liver damage [4]
      • Decreases rate of metabolism
        • Of the rest of paracetamol
        • Of other substrates for hepatic microsomal enzymes

Thioacetamide (TAA)

  • Substitute for H2S with less toxicity and obnoxious smell
  • Repeated exposure produces cirrhosis
  • Uncontrolled entry of Ca+2 ions into hepatocytes [4]
    • Inhibition of oxidative phosphorylation (respiratory metabolism) [4]
  • 1st x increase the RNA and protein content of the nuclear fraction of hepatocytes [4]
    • Varying graded liver damage:
      • Nodular cirrhosis
      • Live cell proliferation
      • Pseudolobules
      • Parenchymal cell necrosis
      • Serum levels of glutamic dehydrogenase increase [4]
        • Indicative of mitochondrial injury [4]
  • 100 mg / kg s.c - acute hepatic damage after 48h [4]
    • Sinusoidal congestion
    • Hydropic swelling with increased mitosis [4]

Rostliny s potencionálně hepatotxickými účinky

Gardenia jasminoides Ellis (Rubiaceae) - Fructus Gardeniae Jasminoidis - Yue Tao - Cape Jasmine Fruit - Zhi Zi - Gardenia Fruit - Gardeniae fructus - Gardénie jasmínovitá [32]

  • Widely used in clinical treatment to cure acute and chronic liver disease [32]
  • Hepatotoxicity has been reported from gardenia and major components [32]
  • Genipin
    • Inhibits UCP2-mediated proton leak
      • Vyšší produkce inzulínu beta-buňkami
      • Exacerbates palmitate-induced hepatic steatosis [39]
  • Tedy asi spíše nevhodná při onemocnění jater

Ricinus communis Linn. - Jatropha - Croton spinosa, Linn. (Euphorbiaceae) - Ricinus africanus Miller - Ricinus badius Rchb. - Ricinus europaeus T. Nees - Ricinus glaucus Hoffmanns. - Ricinus inermis Miller - Ricinus lividus Jacq., Ricinus minor Miller - Ricinus rugosus Miller - Ricinus scaber Bertol. ex Moris - Ricinus speciosus Burm. fil. - Ricinus spectabilis Blume - Ricinus viridis Willd. – skočec obecný - ricín obyčajný


[3]
  • Fresh seeds are very poisonous, which is lost by boiling for 2 hours or by heating 100'C for 20 minutes. [41]
  • Anti-inflammatory [41]
  • Laxative (purgative actions) [41]
  • Anti-neoplastic (anti-cancer) [41]
  • Toxin elimination [41]
  • Root: Characteristically tranquilizers, anti-rheumatic
  • Chemical Ingredients:
    • Seeds:
      • Oil ricinic 40-50%
      • Glyceride of ricinoleic acid content
      • Isoricinoleic acid
      • Oleic acid, linolenic acid, and stearic acid
      • Ricinine (ricin D, ricin ricin)
        • Ricin patří k nejprudším rostlinným jedům [42]
          • Aglutinace (shlukování) červených krvinek [42]
          • Poškozuje játra, ledviny a slezinu [42]
      • Small amount of cytochrome C
      • Lipase and several enzymes [41]
    • Leaves:
      • Kaempferol, kaempferol-3-rutinoside
      • Nicotiflorin
      • Quercetin, isoquercitrin
      • Rutin
      • Astragalin
      • Reynoutrin
      • Ricinine
      • Vit.C 275 mg% [41]
    • Oil:
      • 80% Ricinoleic acid
      • Palmitic acid, stearic acid, linoleic acid, linolenic acid
      • Dihydroxystearic acid
      • Triricinolein 68.2%
      • 28% diricinolein
      • Monoricinolein 2.9%
      • 0.9% nonricinolein [41]
    • Root:
      • Methyltrans-2-decene-4,6,8-triynoate
      • 1-tridecene,5,7,9,11-pentyne-3
      • Beta-sitosterol [41]
  • Vařením oleje ve vodě se zničí jedovaté látky, olej se pak užívá např.:
    • Silné projímadlo
      • Půl až dvě lžíce [41]
    • Při výrobě kosmetických přípravků proti vráskám, působí hojivě [41]
    • Přidává se do svíček [41]
    • I k přípravě jídel [41]
    • Motorový olej, např. do leteckých ale i jiných motorů [41]
    • V textilním a metalurgickém průmyslu [41]

Literatura:

[1] Effect of nickel exposure on peri... [Rev Environ Health. 2007 Apr-Jun] - PubMed - NCBI [Internet]. [citován 31. březen 2013]. Získáno z: www.ncbi.nlm.nih.gov/pubmed/17894205
[2] Dietary modulation of the biotransformation and g... [Toxicology. 2012] - PubMed - NCBI [Internet]. [citován 31. březen 2013]. Získáno z: www.ncbi.nlm.nih.gov/pubmed/22640941
[3] Dietary modulation of the biotransformation and g... [Toxicology. 2012] - PubMed - NCBI [Internet]. [citován 31. březen 2013]. Získáno z: www.ncbi.nlm.nih.gov/pubmed/22640941
[4] Acrolein cytotoxicity in hepatocytes ... [Toxicol Appl Pharmacol. 2012] - PubMed - NCBI [Internet]. [citován 31. březen 2013]. Získáno z: www.ncbi.nlm.nih.gov/pubmed/23026831
[41] Jatropha - ricinus communis Linn. | Health with Natural Remedies [Internet]. [citován 1. duben 2013]. Získáno z: www.wikiherb.info/2012/06/jatropha-ricinus-communis-linn.html
[42] Ricinus communis, Skočec obecný, Ricín obyčajný - Herbář Wendys [Internet]. [citován 1. duben 2013]. Získáno z: botanika.wendys.cz/kytky/K495.php
[4] My Projects: Hepatoprotective Activity [Internet]. [citován 1. duben 2013]. Získáno z: aloksinghpatel.blogspot.cz/2012/12/hepatoprotective-activity.html



O úroveň výše

Poslední aktualizace: 7. 9. 2013 17:17:43
© Dana Maňasková, metabalance.cz
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