Patients with type ii autoimmune hepatitis express functionally intact cytochrome P-450 db1 that is inhibited by LKM-1 autoantibodies in vitro but not in vivo

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Abstract

Liver-kidney microsomal-1 autoantibodies characterize a subgroup of autoimmune chronic active hepatitis. The liver antigen of liver-kidney microsomal-1 antibodies has been identified as cytochrome P450 db1, a microsomal enzyme catalyzing the oxidative metabolism of more than 20 drugs, including debrisoquine, sparteine and bufuralol. A genetic polymorphism (debrisoquin-sparteine polymorphism) is responsible for the lack of P450 db1 protein in the livers of 5% to 10% of Caucasians, leading to impaired drug metabolism and a distinct poor metabolizer phenotype. We investigated whether liver-kidney microsomal-1 positive autoimmune chronic active hepatitis patients express functionally intact P450 db1 in their livers. In four patients with liver-kidney microsomal-1 positive chronic active hepatitis, but not in five patients with various liver-kidney microsomal-1 negative liver diseases, the presence of circulating liver-kidney microsomal-1 antibodies was confirmed by immunofluorescence, radioimmunoassay and immunoblotting analysis using recombinant P450 db1. Moreover, only sera from liver-kidney microsomal-1 positive autoimmune chronic active hepatitis patients strongly inhibited the enzymatic activity of P450 db1 in human liver microsomes in vitro. Immunoblotting detected 50-kd P450 db1 protein in liver biopsy specimens from all patients. The in vivo function of P450 db1 was investigated by determining the metabolic ratio for sparteine and its 2-dehydro and 5-dehydro metabolites in 12-hr urine samples after oral administration of sparteine sulfate. In vivo P450 db1–mediated drug metabolism was of the extensive metabolizer phenotype and did not differ significantly between liver-kidney microsomal-1 positive (metabolic ratio = 1.15 ± 0.32) and liver-kidney microsomal-1 negative (metabolic ratio = 1.18 ± 0.48) patients. Thus patients with liver-kidney microsomal-1 positive chronic active hepatitis express functionally intact P450 db1 in their livers. However, the activity of this enzyme is not significantly diminished in vivo by circulating liver-kidney microsomal-1 autoantibodies that react with the active site of P450 db1 and inhibit its function in vitro. (HEPATOLOGY 1990;12:127–132).

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