PL EN
PRACA ORYGINALNA
The influence of single application of paracetamol and/or N-acetylcysteine on rats in subchronic exposition to trichloroethylene vapours. III. Effect on some isoforms of cytochrome P450 in liver
 
Więcej
Ukryj
1
Department of Histology, Medical University of Silesia, Katowice. Head of Department: R. Wiaderkiewicz MD, PhD, associated professor
2
Department of Proteomics, Medical University of Silesia, Sosnowiec. Head of Department: Prof. A. Plewka MD PhD
3
Department of Toxicology, Medical University, Poznań. Head of Department: Prof. J. Jodynis-Liebert PhD
AUTOR DO KORESPONDENCJI
Andrzej Plewka   

Department of Proteomics, Medical University of Silesia, ul. Ostrogórska 30 41-200 Sosnowiec tel./fax +48 32 364-14-40 e-mail: aplewka@sum.edu.pl
 
Med Srod. 2012;15(4):24–30
 
SŁOWA KLUCZOWE
STRESZCZENIE
Wstęp:
W przypadku przedawkowania paracetamolu, zdolność wątroby do detoksykacji zostaje wysycona i następuje akumulacja toksycznego metabolitu, jaki jest NAPQI. Główne izoformy CYP, uważane za odpowiedzialne za bioaktywację APAP-u i sprzyjające w ten sposób zatruciom wątrobowym, to CYP2E1, CYP1A2 oraz CYP3A4 a u zwierząt dodatkowo izoformy 2B1/2. Celem pracy było zbadanie wpływu paracetamolu i/lub trichloroetylenu na skład wątrobowych izoform cytochromu P450.

Materiał i metody:
Badania wykonano na szczurach, które traktowano trichloroetylenem, paracetamolem i/lub N-acetylocysteiną. We frakcji mikrosomalnej wątroby oznaczano zawartość trzech izoform cytochromu P450, tj., CYP2E1, CYP2B1/2 oraz CYP1A2.

Wyniki:
Paracetamol lekko stymulował CYP2E1 obniżając równocześnie poziom CYP1A2. Trichloroetylen stymulował CYP2B1/2. N-acetylocysteina miała stymulujący wpływ na wszystkie badane izoformy P450. N-acetylocysteina podawana łącznie z badanymi ksenobiotykami prowadziła do wyraźnych wzrostów CYP.

Wnioski:
N-acetylocysteina wykazywała ochronny wpływ na poziomy badanych izoform cytochromu P450, szczególnie, jeśli została podana zaraz po zaprzestaniu ekspozycji na ksenobiotyki.


Introduction:
In case of overdose of paracetamol the,ability of hepatic biotransformation is saturated and accumulation,of toxic metabolite – NAPQI takes place. Main,CYP isoforms considered to be responsible for bioactivation,of APAP and promoting the same liver intoxication are,CYP2E1, CYP1A2, CYP3A4 and in animals 2B1/2 isoforms additionally. Purpose of this work was examination of paracetamol influence and/or trichloroethylene on the composition of hepatic cytochrome P450 isoforms.

Material and Methods:
Tests were carried out on rats which were treated with trichloroethylene, paracetamol and/or N-acetylcysteine. In the microsomal fraction content of three isoforms of cytochrome P450 i.e. CYP2E1, CYP2B1/2 and CYP1A2 were determined.

Results:
Paracetamol slightly stimulated CYP2B1/2 lowering simultaneously level ofCYP1A2. Trichloroethylene stimulated CYP2B1/2. N-acetylcysteine stimulated all tested P450 isoforms. N-acetylcysteine given together with examinated xenobiotics induced studied P450 isoforms.

Conclusions:
N-acetylcysteine demonstrated a protective effect on studied CYP isoforms especially when was given upon termination of xenobiotics exposure.

 
REFERENCJE (32)
1.
Vermeulen N.P.E., Bessems J.G.M., Van de Straat R.: Molecular aspects of paracetamol induced hepatotoxicity and its mechanism based prevention. Drug Metab Rev 1992; 24: 367-407.
 
2.
Tonge R.P., Kelly E.J., Bruschi S.A., i wsp.: Role of CYP1A2 in the hepatotoxicity of acetaminophen: Investigations using CYP1A2 null mice. Toxicol Appl Pharmacol 1998; 153: 102- 108.
 
3.
Dong H., Haining R.L., Thummel K.E., i wsp.: Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metab Dispos 2000; 12: 1397-1400.
 
4.
Cai H., Guengerich F.P.: Reaction of trichloroethylene and trichloroethylene oxide with cytochrome P450 enzymes: Inactivation and sites of modification. Chem Res Toxicol 2001; 14: 451-458.
 
5.
Manyike P.T., Kharasch E.D., Kalhorn T.F., i wsp.: Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000; 67: 275-282.
 
6.
Zaher H., Buters J.T., Ward J.M., i wsp.: Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol Appl Pharmacol 1998; 152: 193-199.
 
7.
Laine J.E., Auriola S., Pasanen M., i wsp.: Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica 2009; 39: 11-21.
 
8.
Nakajima T., Wang .RS., Elovaara E., i wsp.: A comparative study on the contribution of cytochrome P450 isozymes to metabolizm of benzene, toluene and trichloroethylene in rat liver. Biochem Pharmacol 1992; 43: 251-257.
 
9.
Plewka A., Czekaj P., Kamiński M., i wsp.: Circadian changes of cytochrome P450-dependent monooxygenase system in the rat liver. Pol J Pharmacol Pharm 1992; 44: 655-661.
 
10.
Czekaj P., Plewka A., Kamiński M., i wsp.: Daily and circadian rhythms in the activity of mixed function oxidases system in rats of different age. Biol Rhythm Res 1994; 25: 67-75.
 
11.
Dallner G.: Isolation of rough and smooth microsomes – general. Methods Enzymol 1974; 32: 191-215.
 
12.
Laemmli U.K.: Cleavage of structural proteins during the assembly of the head of bacteriophage T4 Nature 1970; 227: 680-685.
 
13.
Raucy J.L., Lasker J.M., Lieber C.S., i wsp.: Acetaminophen activation by human liver cytochromes P450 IIE1 and PIA2. Archiv Biochem Biophys 1989; 271: 270-283.
 
14.
Chen W., Koenigs L.L., Thompson S.J, i wsp.: Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. Chem Res Toxicol 1998; 11: 295-301.
 
15.
Lee S.S.T., Buters J.T.M., Pineau T., i wsp.: Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 20: 12063-12067.
 
16.
James L.P., Mayeux P.R., Hinson J.A.: Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003; 31: 1499-1506.
 
17.
Lee W.M.: Review article: drug-induced hepatotoxicity. Aliment Pharmacol Ther 1993; 7: 477-485.
 
18.
Ostapowicz G., Fontana R.J., Schiodt F.V., i wsp.: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002; 137: 947- 954.
 
19.
Wang R.-S., Nakajima T., Tsuruta H., i wsp.: Effect of exposure to four organic solvents on hepatic cytochrome P450 isozymes in rat. Chem-Biol Interact 1996; 99: 239-252.
 
20.
Zielińska-Psuja B., Orłowski J., Plewka A., i wsp.: Metabolic interactions in rats treated with acetylsalicylic acid and trichloroethylene. Pol J Environm Studies 1999; 8: 319-325.
 
21.
Hanioka N., Omae E., Yoda R., i wsp.: Effect of trichloroethylene on cytochrome P450 enzymes in the rat liver. Bull Environm Contam Toxicol 1997; 58: 628-635.
 
22.
Miller R.E., Guengerich F.P.: Metabolism of trichloroethylene in isolated hepatocytes, microsomes, and reconstituted enzyme systems containing cytochrome P-450. Cancer Res 1983; 43: 1145-1152.
 
23.
Guengerich F.P., Kim D.H., Iwasaki M.: Role of human cytochrome P-450IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 1991; 4: 168-179.
 
24.
Casley W.L., Menzies J.A., N. Mousseau N., i wsp.: Increased basal expression of hepatic Cyp1a1 and Cyp1a2 genes in inbred mice selected for susceptibility to acetaminophen-induced hepatotoxicity, Pharmacogenetics 1997; 7: 283-293.
 
25.
Comporti M., Maellaro E., Del Bello B., i wsp.: Glutathione depletion: its effects on other antioxidant systems and hepatocellular damage. Xenobiotica 1991; 21: 1067-1076.
 
26.
Vendemiale G., Grattagliana I., E. Altomare E., i wsp.: Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat, Biochem Pharmacol 1996; 52: 1147-1154.
 
27.
Snawder J.E., Roe A.L., Benson R.W., i wsp.: Loss of CYP2E1 and CYP1A2 activity as a function of acetaminophen dose: relation to toxicity. Biochem Biophys Res Commun 1994; 203: 532-539.
 
28.
Sarich T., Kalhorn T., Magee S., i wsp.: The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin. Clin Pharmacol Ther 1997; 62: 21-28.
 
29.
Hazai E., Vereczkey L., Monostory K.: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun 2002; 291: 1089-1094.
 
30.
Thummel K.E., Lee C.A., Kunze K.L., i wsp.: Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 1993; 45: 1563-1569.
 
31.
Tan S.C., New L.S., Chan E.C.: Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine. Toxicol Lett 2008; 180: 174-181.
 
32.
Wolf K.K., Wood S.G., Allard J.L, i wsp.: Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: comparison of wild-type and Cyp2e1(-/-) mice. Drug Metab Dispos 2007; 35 :1223-1231.
 
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