Phase I and phase II xenobiotic biotransformation in different inbred strains of rats: study in immobilized perfused hepatocytes.
The present study was designed to compare phase I and phase II biotransformation reactions in immobilized perfused hepatocytes as a cellular system obtained from inbred rat strains which represent models for some cardiovascular diseases, namely, spontaneously hypertensive rats (SHR), rats sensitive and resistant to isoprenaline-induced myocardial lesions (IS and IR, respectively) as compared to Wistar rats (W). The biotransformation kinetics for hexobarbital (HX), 7-ethoxycoumarin (7-EC), 1-chloro-2,4-dinitrobenzene (CDNB) and 4-nitrophenol (4-NP) were followed up in the hepatocyte perfusate. W and SHR rat hepatocytes have metabolized HX at a higher rate than those of the IR and IS strains. Hepatocytes from the W strain exhibited a higher rate of 7-EC deethylation activity compared to hepatocytes obtained from the IR or IS strains. Hepatocytes obtained from SHR and IR rats showed the highest glutathione-S-transferase (GST) activity towards CDNB compared to the IS or W strain. 4-NP disappearance was higher in the perfusion medium of hepatocytes obtained from the W and IS strains compared to the IR strain. These significant differences in drug biotransformation between various studied strains, which may be genetically determined, can be well demonstrated by using an efficient drug metabolizing model of the immobilized perfused hepatocytes. The importance of these differences should be considered during the study of the experimental therapy of the relevant disease as obtained from the specific experimental strain, where it may be expected that the pharmacokinetic profile of a drug in vivo and consequently its pharmacodynamic or toxic effects will be strain dependent.
Hynie
S
S
Institute of Pharmacology, 1st Medical Faculty, Charles University, Prague, Czech Republic.
Kren
V
V
Mráz
M
M
Farghali
H
H
D000818:Animals; D001711:Biotransformation; D018914:Cells, Immobilized; D003374:Coumarins / Q000493:pharmacokinetics; D004137:Dinitrochlorobenzene / Q000493:pharmacokinetics; D004351:Drug Resistance / Q000235:genetics; D006591:Hexobarbital / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000493:pharmacokinetics; D010477:Perfusion; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013045:Species Specificity; D015262:Xenobiotics / Q000493:pharmacokinetics*
D003374:Coumarins; D004137:Dinitrochlorobenzene; D009596:Nitrophenols; D015262:Xenobiotics; C017299:7-ethoxycoumarin; D006591:Hexobarbital; D007545:Isoproterenol; C024836:4-nitrophenol