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Mechanism of cholestasis

1971; Elsevier BV; Volume: 14; Issue: 2 Linguagem: Inglês

10.1016/0014-4800(71)90070-0

1096-0945

Helmut Denk, John B. Schenkman, Paolo Bacchin, Ferenc Hutterer, Fenton Schaffner, Hans Pópper,

Biochemical and Molecular Research

Synthetic nonionic and anionic detergents interact with the cytochrome P-450 dependent microsomal biotransformation system in three somewhat overlapping stages depending on dose and time of exposure. In the first stage, the detergents bind to P-450, presumably to a lipoprotein region (binding site I). This is reflected in a spectral change of P-450, the enhancement of the P-450 reductase, and the competitive inhibition of the metabolism of other Type I substrates, like aminopyrine. In the second stage the mixed inhibition of the aminopyrine demethylation without a proportional loss of P-450 suggests a blocking or solubilization of the lipoprotein binding site. In the third stage, degradation of P-450 and solubilization of P-450 reductase reflects the breakdown of the enzyme system. These stages correspond to the effect on microsomes of dihydroxy bile acids in vitro and to some degree of bile duct ligation in vivo. These observations suggest a detergent effect of bile acids as an explanation of the alterations of the endoplasmic reticulum in cholestasis.