Selective destruction of cytochrome P-450d and associated monooxygenase activity by carbon tetrachloride in the rat.
1. The effects of acute treatment of 3-methylcholanthrene (MC)-induced rats with carbon tetrachloride (CCl4) on the content and activity of the polycyclic aromatic hydrocarbon-inducible forms of cytochrome P-450 (P-450c and P-450d) in liver and kidney have been determined. 2. Post-treatment of MC-induced rats with CCl4 in vivo decreased the specific content of total, spectrally determined, P-450 in both hepatic and renal microsomes, by 60% and 40%, respectively. CCl4 treatment destroyed almost all of the hepatic P-450d (specific content after 6 h, less than 2% of control), but had no effect on P-450c, which increased slightly over the 6 h, to 30% above control values. 3. Immunocytochemical measurements demonstrated greater loss of P-450d from the centrilobular and midzonal than from periportal regions of the liver. 4. Hepatic phenacetin O-deethylase, an activity catalysed specifically by P-450d in this tissue, was dramatically decreased following administration of CCl4 to MC-induced rats. Loss of monooxygenase activity was highly correlated with the decrease in P-450d content (r = 0.947, P less 0.001). Aryl hydrocarbon hydroxylase activity of liver, catalysed almost entirely by P-450c, was unchanged and neither activity was affected in kidney. 5. Treatment of MC-induced rats with CCl4 causes a selective loss of hepatic P-450d and associated monooxygenase activities. Phenacetin O-deethylation is catalysed specifically by P-450d in liver, but not in kidney. The mechanism for this destruction of P-450d may be suicide activation of CCl4, but the rate of such activation appears to be much lower than with P-450b. Alternatively, P-450d may be particularly sensitive, and P-450c particularly resistant, to the active metabolite of CCl4 diffusing from a distant site of formation.
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, U.K.
D
D
Sesardic
K J
KJ
Rich
R J
RJ
Edwards
D S
DS
Davies
A R
AR
Boobis
D000818:Animals; D015153:Blotting, Western; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000503:physiopathology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology; D003720:Densitometry; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases