In micronodular cirrhosis, hepatocytes retain a normal C-25 hydroxylation capacity toward vitamin D3: a study using the rat carbon tetrachloride-induced cirrhotic model.
To test further the competence of the cirrhotic liver to metabolize vitamin D3 at C-25, hepatocytes were isolated from controls and from CCl4-induced cirrhotic rat livers, as well as from partially hepatectomized rats. The transformation of D3 into 25-hydroxyvitamin D3 was studied in the presence of 10(7) hepatocytes at D3 concentrations of 20 nmol/L to 15.4 mumol/L. Histologically, micronodular cirrhosis was present in all CCl4-treated rats, whereas controls had normal livers; portal venous pressure (p less than 0.008) and intrahepatic collagen content (p less than 0.0001) were significantly increased in CCl4-treated rats, whereas no difference was found between the two groups in the total and ionized serum calcium, D3 metabolites, ALT, AST and alkaline phosphatase. Cytochrome P-450 was 0.27 +/- 0.02 and 0.25 +/- 0.02 nmol/10(6) hepatocytes in controls and cirrhotic rats (N.S.), and it significantly increased in both groups after phenobarbital or 3-methylcholanthrene administration (p less than 0.0001). 25-Hydroxyvitamin D3 formation was best described by power law equations and varied between 0.02 +/- 0.0004 and 29.57 +/- 2.8 in controls, and 0.024 +/- 0.0004 and 32.0 +/- 7.0 pmol.hr-1.10(6) hepatocytes-1 in cirrhotic rats. No statistically significant difference was found in the slopes of the 25-hydroxyvitamin D3 formation, but the y-axis intercept was found to be lower in cirrhotic rats under basal resting conditions (p less than 0.005). Inducers of the mixed function oxidases significantly increased 25-hydroxyvitamin D3 formation in controls as well as in cirrhotic rats (p less than 0.005). Moreover, both groups were found to respond similarly to the addition of modulators of the enzyme such as the calcium ionophore A23187 and parathyroid hormone. Partial hepatectomy was also without effect on the activation of D3. Furthermore, the cell sequestration of D3 was also found to be unperturbed in hepatocytes obtained from either cirrhotic or partially hepatectomized livers. The data indicate that in well-compensated micronodular cirrhosis, the C-25 hydroxylation of D3 is generally intrinsically normal at the cellular level and that it also remains fully responsive to in vivo and in vitro modulators of its activity.
Dubé
C
C
André-Viallet Clinical Research Center, St. Luc Hospital, Montreal, Quebec, Canada.
Vallières
S
S
Ethier
C
C
Benbrahim
N
N
Tremblay
C
C
Gascon-Barré
M
M
D000818:Animals; D002112:Calcifediol / Q000378:metabolism; D002251:Carbon Tetrachloride; D002762:Cholecalciferol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006900:Hydroxylation; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002762:Cholecalciferol; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D002112:Calcifediol; D010634:Phenobarbital