The effect of alcoholic cirrhosis on the activities of microsomal aldrin epoxidase, 7‐ethoxycoumarin O‐de‐ethylase and epoxide hydrolase, and on the concentrations of reduced glutathione in human liver.

Abstract

The University of Newcastle-upon-Tyne, Newcastle-upon-Tyne 1 Activities of the microsomal mono-oxygenases 7-ethoxycoumarin O-de-ethylase (EOC) and aldrin epoxidase (AE), together with microsomal epoxide hydrolase (EH) activity and concentrations of reduced glutathione (GSH) have been measured in liver from patients with alcoholic cirrhosis and in normals. 2 Activities of both mono-oxygenases were significantly reduced in alcoholic cirrhosis. EOC activity (pmol 7-OH coumarin formed/mg microsomal protein/min) was 108.0 + 10.6 (n = 8) in normals and 60.9 + 11.6 (n = 8) in alcoholic cirrhosis (P < 0.01). AE activity (pmol dieldrin formed/mg microsomal protein/min) was 58.9 + 9.5 (n = 11) in normal liver biopsies and 29.9 + 8.6 (n = 9) in alcoholic cirrhosis (P < 0.05). 3 Microsomal EH activity (nmol styrene glycol formed/mg microsomal protein/min) was similar in normals (39.2 + 4.4, n = 11) and alcoholic cirrhosis (40.5 + 9.1, n = 6). 4 GSH concentrations (,ug GSH/g liver tissue) were lower (P < 0.01) in alcoholic cirrhosis (792 + 73, n = 10) compared to normals (1182 ± 76, n = 6).

The metabolism of 7‐ethoxycoumarin in human liver microsomes and the effect of primary biliary cirrhosis: implications for studies of drug metabolism in liver disease.

“…There was a three fold variation in enzyme activity in control subjects, and this was even greater in some of the disease groups. We have previously noted similar variation in both normal liver and in alcoholic cirrhotics, using both 7-ethoxycoumarin and aldrin as probe substrates (Woodhouse et al, 1984(Woodhouse et al, , 1983, and Boobis et al (1980) found that aryl hydrocarbon hydroxylase activity in human liver biopsies varied more than three fold. The main finding of the study, however, is that the histologically graded severity of the liver disease appears to be a relatively minor determinant of 7-ethoxycoumarin O-de-ethylation in PBC.…”

“…Biopsies were homogenised and microsomal fractions prepared as previously described (Woodhouse et al, 1983). Enzyme activity was determined by measuring the rate of formation of 7-hydroxycoumarin from the substrate, 7-ethoxycoumarin (Greenlee & Poland, 1978).…”

“…Using probe substrates, the in vitro activities of these enzymes have been shown to be impaired in liver tissue from patients with alcoholic cirrhosis (Woodhouse et al, 1983(Woodhouse et al, , 1984 and in heterogeneous groups of subjects with liver disease of mixed aetiology (Brodie et al, 1981;Farrell et al, 1979). The interpretation of such findings is often rendered difficult by the variable nature of the liver disease, and by concomitant ethanol exposure and drug intake.…”

7-Ethoxyresorufin deethylase (EROD) in human liver —The effect of alcoholic liver disease

“…The findings of reduced activity in patients with severe alcoholic liver disease compared to controls is compatible with our previous work (Woodhouse et al 1983(Woodhouse et al , 1984, in which the activities of the microsomal monooxygenases, aldrin epoxidase, and 7-ethoxycoumarin 0-deethylase, were shown to be reduced in patients with severe alcoholic cirrhosis. The present study is of particular interest because the cytochrome P-450 forms involved are probably responsible for the activation of a large number of environmental carcinogens to their ultimate carcinogenic form.…”

Ethoxyresorufin O‐deethylation by human liver microsomes.

“…Ethoxycoumarin-O-deethylation (ECOD) ECOD was measured as described previously (Woodhouse et al, 1983) at high (1000 FM) and low (5 FM) substrate concentrations.…”