Rat liver slices

Togashi, H., Shinzawa, H., Wakabayashi, H., Nakamura, T., Yong, H., Yamada, N., Ukai, K., Okuyama, Y., Takahashi, T. and Ishikawa, M. (1990). Superoxide is involved in the pathogenesis of paraquat-induced injury in cultured rat liver slices. Hepatology 14, 707-714. 

In rat liver slices, evidence also supports the roles of QMs in mediating the toxicity of a series of 4-methylphenols.24 The potency correlates with rates of QM formation in the order 2-bromo-4-methylphenol > 4-methylphenol = DMP > TMP > 2-methoxy-4-methylphenol. None of these compounds contain two bulky ortho substituents, so as discussed earlier the corresponding QMs are expected to be highly reactive. The authors suggested that differences in the reactivities of these QMs determine their relative toxic potencies as electron-donating substituents on the ring stabilize the QM and thereby reduce its toxicity (e.g., 2-methoxy-4-methylphenol is less toxic than DMP) and conversely, electron-withdrawing substituents destabilize QMs and enhance toxicity (e.g., 2-bromo-4-methylphenol is more potent than DMP). 

Thompson, D. C. Perera, K. Krol, E. S. Bolton, J. L. o-Methoxy-4-alkylphenols that form quinone methides of intermediate reactivity are the most toxic in rat liver slices. Chem. Res. Toxicol. 1995, 8, 323-327. 

Most of the information on the metabolism of hexachloroethane has been collected by in vitro techniques using rat liver slices or rat liver microsomes. Figure 2-3 summarizes the results of these studies. The identification of tetrachloroethene and pentachloroethane as the initial metabolites of hexachloroethane metabolism in vitro agrees with in vivo data from sheep that were orally exposed to doses of 500-1,000 mg/kg hexachloroethane (Fowler 1969b). 

It will readily be seen in our series of w-fluorocarboxylic acids, that when n is odd, / -oxidation would yield the toxic fluoro-acetic acid, whereas when n is even, the compound would presumably be oxidized only as far as the non-toxic yff-fluoro-propionic acid.1 The pharmacological results obtained are in complete accord with this hypothesis, and provide verification, of a kind not hitherto achieved, of the process of / -oxidation in the living animal body. However, Weinhouse, Medes and Floyd2 have inoculated rat-liver slices with one or two fatty acids containing isotopic carbon, and have obtained some evidence for a process of /7-oxidation. 

Azri-Meehan S, Mata HP, Gandolfi AJ, et al. 1992. The hepatotoxicity of chloroform in precision-cut rat liver slices. Toxicology 73(3) 239-250. 

In order to investigate the possibilities and limitations of the use of precision-cut liver slices prepared with a mechanical sheer in drug transport studies, different aspects of the mechanism of uptake of several classes of drugs in human and rat liver slices were investigated in our laboratory. Four model compounds which enter hepatocytes via entirely differ-... 

Figure 12.4. Rhodamine B (25 M) distribution in the cross-section of a rat liver slice ( 250 frM) after 5 min incubation. Fluorescence microscopy, bar = 100 pM.

Digoxin uptake into rat hver shces showed a temperature-dependent component, compatible with the involvement of carrier-mediated uptake mechanisms. Quinine markedly inhibited the uptake of digoxin, in contrast to its diastereomer quinidine, which only slightly inhibited the digoxin uptake in rat liver slices. This stereoselective inhibition is in line with results obtained in isolated rat hepatocytes and isolated perfused rat hvers [90,91]. These results were also found after cryopreservation of the slices, indicating that carrier-specific phenomena can be studied after cryopreservation [92]. 

Figure 12.8. NO production in rat liver slices after incubation in the absence or presence of 100 pg ml LPS for different time periods. The NO production is measured as nitrate/nitrite (NO ) concentrations in the medium (pM). Control ( ) and + 100 pg ml" LPS ( ). Data are expressed as mean SEM of four experiments. p < 0.005 represents a significant increase in NO production by liver slices due to stimulation by LPS.

Studies similar to those described above are now being carried out in human liver slices. LPS induction in human liver slices also increased TNFa production to the same extent as was found in rat liver slices [104] (Figure 12.10). Human liver slices also produced IL-6, IL-8 and IL-ip, although the latter to a lesser extent than that observed in the liver slices of rat origin. However, human liver slices produced less NO after LPS stimulation than those of the rat. More experiments will be undertaken to elucidate this species difference. 

Figure 12.9. (a) TNFa production by rat liver slices (n = 9) after stimulation with 100 pg ml LPS for 24 h in either the presence or absence of dexamethasone (D). Vehicle consists of PBS. p < 0.05 versus vehicle + LPS. (b) TNFa production by rat liver slices (n = 9) after LPS stimulation for 24 h with or without Dexaio-HSA (DH). Vehicle contains PBS and an equimolar amount of HSA. p < 0.05 versus vehicle + LPS. 

Figure 12.10. Production of TNFa by human and rat liver slices in culture medium after 24 h stimulation with or without 100 (ig mH LPS. White bar control black bar 100 jig ml" LPS present. Data are the mean of four experiments SEM. p < 0.05 versus control.

Fisher R, Smith PF, Sipes IG, et al. 1990. Toxicity of chlorobenzenes in cultured rat liver slices. 

Simpson, M.V. (1953). The release of labeled amino acids from the proteins of rat liver slices. J. Biol. Chem. 201, 143-154. 

Thompson DC, Perera K, Fisher R, et al Cresol isomers comparison of toxic potency in rat liver slices. Toxicol Appl Pharmacol 125 51-58, 1994... 

Azri S, Mata HP, Gandolfi AJ, Brendel K. 1991. CCKinduced cytochrome P-450 loss and lipid peroxidation in rat liver slices. Biol Reactive Intermediates 669-674. 

Wolfgang GH, Donarski WJ, Petry TW. 1990. Effects of novel antioxidants on carbon tetrachloride-induced lipid peroxidation and toxicity in precision-cut rat liver slices. Toxicol AppI Pharmacol 106 63-70. 

Wijeweera, J.B., Gandolfi, A.J., Badger, D.A., Sipes, I.G. Brendel, K. (1996) Vitamin A potentiation of vinylidene chloride hepatotoxicity in rats and precision cut rat liver slices. Fundam. appl. Toxicol., 34, 73-83... 

Carr et al., 1993). The neutral loss scan mode is used as a class identifier to also screen components that contain a common substructure. Barbuch et al. demonstrated this approach for the class identification of phytoestrogens (Barbuch et al., 1989), using thermospray ionization (TSI)-LC/MS/MS. Brownsill et al. used a similar electrospray ionization (ESI)-LC/MS/MS approach for the analysis of metabolites in rat liver slices (Brownsill et al., 1994). 

B. 1994. The application of electrospray and neutral-loss mass spectrometry to the identification of the metabolites of S12813 in rat liver slices. Rapid Commun. Mass Spectrom., 8,361-365. 

Fishman s point of view was based largely on the following observations. (a) Glucuronogenic substances, such as borneol, increase the /3-D-glucuronidase activity of the liver, kidney, and spleen, (b) The conjugation of phenol by rat-liver slices, inhibited by monoiodoacetate, is... 

The 5a-reductase enzyme was initially identified in the early 1950s by Schneider and co-workers in studies examining the metabolism of des-oxycorticosterone in rat liver slices (Schneider and Hortsmann, 1951 Schneider, 1952). Subsequent studies (Forchielli and Dorfman, 1952 Tomkins, 1957 McGuire and Tomkins, 1960 McGuire et al., 1960) demonstrated that the enzyme catalyzed the reduction of a variety of steroid substrates, including testosterone, which can be reduced to DHT (Fig. 1). 

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