Selective Destruction of Cytochrome P-450d and Associated Monooxygenase Activity by Carbon Tetrachloride in the Rat

Abstract

1. The effects of acute treatment of 3-methylcholanthrene (MC)-induced rats with carbon tetrachloride (CCI₄) 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 6h, <2% of control), but had no effect on P-450c, which increased slightly over the 6h, 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<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.