Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis.
The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed. Fibrotic bands were progressively more prominent at 20 and 25 weeks and cirrhosis was established by 30 weeks of dietary intake. Portal pressure, as measured by saline manometry and indicated by splenomegaly, appeared to increase gradually after 6 weeks and by 25 weeks values were significantly greater than controls. The microsomal content of P450 2C11 and its associated steroid 16 alpha-hydroxylase activity were unchanged at 6 weeks but were decreased to around 30% of control from 10 weeks of intake of the choline-deficient diet to the end of the experimental period (30 weeks). Serum bile acids were approximately 2-fold greater in choline-deficient rats from 10 weeks. Similarly, serum estradiol concentrations were elevated (to 2.5-fold of control) in male rats after 10 weeks intake of the choline-deficient diet; this increase was sustained in 30-week cirrhotic rats. On the other hand, there was no evidence of altered serum testosterone until 30 weeks of dietary deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Murray
M
M
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Cantrill
E
E
Mehta
I
I
Farrell
G C
GC
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000097:blood; D001835:Body Weight; D002796:Choline Deficiency / Q000150:complications* / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004958:Estradiol / Q000097:blood; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009929:Organ Size; D051381:Rats; D011919:Rats, Inbred Strains; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D001647:Bile Acids and Salts; D013739:Testosterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D000469:Alkaline Phosphatase