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.