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]

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

• 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: