(1973). Carbon Tetrachloride Hepatotoxicity: An Example of Lethal Cleavage. CRC Critical Reviews in Toxicology: Vol. 2, No. 3, pp. 263-297.

Carbon tetrachloride hepatotoxicity: an example of lethal cleavage

Three models of free radical-induced cell injury.

The oxygen reductase and xenobiotic reductase activities of cytochrome P450 (P450) are reviewed. During the oxygen reductase activity of P450, molecular oxygen is reduced to superoxide anion radicals (O−2) most likely by autooxidation of a P450 ferric-dioxyanion complex. The formation of reactive oxygen species (O−2, hydrogen peroxide, and, notably, hydroxyl free radicals) presents a potential toxication pathway, particularly when effective means of detoxication are lacking. Under anaerobic conditions, P450 may also be involved in the reduction of xenobiotics. During the xenobiotic reductase activity of P450, xenobiotics are reduced by the ferrous xenobiotic complex. After xenobiotic reduction by P450, xenobiotic free radicals are formed that are often capable of reacting directly with tissue macromolecules. Unfortunately, the compounds that are reductively activated by P450 have little structural similarity. The precise molecular mechanism underlying the xenobiotic reductase activity of P450 is, ...

Oxygen and xenobiotic reductase activities of cytochrome P450.

Interest in the oxidation of xenobiotics catalyzed by flavin-containing monooxygenases has expanded dramatically over the past decade. Studies on their exceptional substrate range, wide tissue distribution, and the existence of multiple forms are perhaps the major developments that have stimulated recent work on these enzymes. In addition, the reports by Smith and his associates on the polymorphism of the N-oxygenation of trimethylamine (1) and nicotine (2) in humans apparently due to a genetic defect in one or more of the flavin-containing monooxygenases has fueled further interest in the role of these enzymes in the metabolism of xenobiotics. This review focuses primarily on recent work on the number of isoforms (based largely on differences in primary structures deduced from cDNAs) present in major organs of entry, possible methods for estimating substrate specificity and activity of different isoforms in crude tissue preparations, and methods for manipUlating hepatic concentration (activity) of flavin-containing monooxygenases with dietary xenobiotics. The latter work, while still in very early stages, will undoubtedly have a significant impact on this area of drug metabolism by providing a convenient model for assessing the effect of changes in the concentration of these enzymes on the metabolism of a specific

Recent Studies on the Structure and Function of Multisubstrate Flavin-Containing Monooxygenases

Consequences of cadmium toxicity in rat hepatocytes: mitochondrial dysfunction and lipid peroxidation.

1.

In reduzierten und anaeroben Suspensionen von Kaninchenlebermikrosomen werden 2% von zugegebenem CCl4 (1 mM) innerhalb von 5 min zu CHCl3 umgewandelt. Die Bildung von CHCl3 wird durch Metyrapon um 50%, durch CO um 75% und durch O2 um 95% gehemmt.




2.

Orale Gaben von 2,5 ml/kg CCl4 an Ratten bewirken innerhalb der ersten 3 Std einen Abfall des endoplasmatischen Cytochroms P-450 um 30 bis 40%. Diese Verringerung wird durch Behandlung der Ratten mit Metyrapon, Desipramin, Piperonylbutoxid, Disulfiram oder Silymarin nicht verhindert.




3.

Die Abnahme von Cytochrom P-450 kann in vitro durch aerobes Inkubieren von isolierten Lebermikrosomen mit NADPH in Gang gesetzt werden und wird durch CCl4 weiter beschleunigt. Zwischen dem Ausmas der Lipidperoxidation und der Abnahme von Cytochrom P-450 wurde eine gute Korrelation gefunden. ADTA oder GSH verhindern die Lipidperoxidation. Infolgedessen andert sich der Gehalt an Cytochrom P-450 sogar in Gegenwart von CCl4 gegenuber den Kontrollen nicht. UV-Bestrahlung von Mikrosomensuspensionen bewirkt Lipidperoxidation und schnelle Zerstorung von Cytochrom P-450.




4.

Wahrend der Inkubation von Lebermikrosomen mit Linolensaure und Lipoxygenase aus Sojabohnen wurde eine ahnliche Beziehung zwischen der Abnahme von Cytochrom P-450 und der Lipidperoxidation beobachtet. Zugabe von Linolensaure oder Lipoxygenase allein hatte keine Wirkungen. Die Untersuchungen und Befunde sprechen fur einen gekoppelten Mechanismus der Lipidperoxidation mit gleichzeitiger oxidativer Zerstorung des Ham-Anteils.

Hellmer Kh

Papers

Bildung von Chloroform aus Tetrachlorkohlenstoff in Lebermikrosomen, Lipidperoxidation und Zerstörung von Cytochrom P-450

Perinatal development of tertiary amine N-oxidation and NADPH cytochrome C reduction in rat liver microsomes.

[Formation of chloroform from carbon tetrachloride in liver microsomes, lipid peroxidation and destruction of cytochrome P-450].