Fibrotic process and drug metabolism in alcoholic liver disease.

The effect of fibrosis on drug metabolism in alcoholic liver disease was evaluated in a comparison of the concentrations of serum aminoterminal propeptide of type III procollagen and basement membrane (BM; 7S domain of type IV collagen and laminin) antigens with in vitro (cytochrome P-450) and in vivo (antipyrine) drug metabolism in 67 alcoholics classified by liver histology. Alcoholics with intact or fatty liver had rapid or normal drug metabolism and normal collagen metabolism. Alcoholics with a fatty liver plus fibrosis or active cirrhosis had reduced drug metabolism and elevated levels of serum markers for collagen and BM metabolism. Alcoholics with inactive cirrhosis who had received therapy with enzyme inducers had a tendency toward normal drug and collagen metabolism parameters. Antipyrine metabolism, but not P-450 content, was related to the levels of serum type III collagen and BM markers. The fibrotic process, especially BM formation, creates a mechanical barrier that may prevent contact between blood and hepatocytes, thus delaying substrate availability.

Relationship between lipid composition and drug metabolizing capacity of human liver.

The relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearson's product moment correlation coefficient) = 0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r = -0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.

Serum low-density lipoprotein and high-density lipoprotein cholesterol, and liver size in subjects on drugs inducing hepatic microsomal enzymes.

Serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentration and the ratio between them, major risk factors of coronary heart disease, and liver size were investigated in 18 subjects who were on enzyme-inducing anticonvulsants, phenytoin alone or in combination with phenobarbital and/or carbamazepine. The subjects with a high liver cytochrome P-450, indicating hepatic microsomal enzyme induction, who showed an increase in liver size, had an elevated high-density lipoprotein concentration and high-density lipoprotein cholesterol/total cholesterol ratio, and a reduced low/high-density lipoprotein cholesterol ratio. The high-density lipoprotein cholesterol concentration and its ratio to total cholesterol were directly and related to the ratio between low and high-density lipoprotein cholesterol were inversely related to the extent of liver enlargement. The serum cholesterol distribution profile associated with an increase in liver size was typical of subjects with a low risk of coronary heart disease. The results suggest that enzyme-inducers, such as phenytoin and phenobarbital, induce structural and functional changes in hepatocellular membranes associated with liver enlargement and cholesterol distribution characteristic of low susceptibility to atherosclerotic vascular disease.

Plasma HDL cholesterol and blood glucose in non-insulin-dependent diabetics related to liver lipids and microsomal enzyme activity.

The major lipid predictors of coronary events, plasma high density lipoprotein cholesterol (HDL-C) and the HDL-C/total cholesterol (T-C) ratio, and blood glucose (BG) in 12 subjects with non-insulin-dependent diabetes mellitus were related to hepatic lipids, proteins and microsomal enzyme activity assessed by liver cytochrome P-450 (P-450). Non-insulin-dependent diabetics had low HDL-C/T-C ratio, liver phospholipid (PL) and P-450 and high serum and liver triglyceride (TG) concentrations. Plasma HDL-C was decreased, and BG high, especially in subjects with reduced PL and P-450. The HDL-C/T-C ratio was directly proportional to liver PL and P-450 and unrelated to hepatic TG. Increases in liver PL and microsomal enzyme activity may be favorably reflected both in cholesterol distribution and diabetic control.

Drug metabolism in diabetic subjects with fatty livers.

The effect of fatty degeneration of liver parenchyma on drug metabolism was investigated in 21 obese non-insulin-dependent diabetic subjects by measuring plasma antipyrine kinetics, hepatic cytochrome P-450, liver size and the extent of fatty infiltration. The hepatic drug metabolising capacity, as measured by total antipyrine clearance and the estimated total amount of cytochrome P-450, was at the same level as in non-diabetic control subjects with normal livers. Relative antipyrine clearance (per unit weight of liver) and cytochrome P-450 concentrations were significantly lower in the diabetics than in controls. The extent of fatty infiltration correlated poorly with the indices of drug metabolism. In non-insulin-dependent diabetics, slight to moderate hepatic fatty infiltration, without more serious structural distortion interfering with hepatic blood flow or hepatocellular function, seems to have only a minor influence on drug metabolism.

Inverse relationship of serum LDL cholesterol and the LDL/HDL cholesterol ratio to liver microsomal enzyme induction in man.

The association of serum LDL cholesterol and the LDL/HDL cholesterol ratio, the major positive risk factors of coronary heart disease, to hepatic microsomal enzyme induction assessed by liver cytochrome P-450, was investigated in 18 subjects who were treated with inducing anticonvulsants. In subjects with normal liver histology, LDL cholesterol and the LDL/HDL cholesterol ratio were inversely proportional to the magnitude of induction. Strong induction was associated with a low LDL cholesterol level. The serum cholesterol distribution profile and the low LDL/HDL cholesterol ratio associated with induction are characteristic of low risk of coronary heart disease. The present findings support studies showing a positive association between HDL cholesterol and induction and suggesting a new therapeutic approach to atherosclerotic vascular disease.

Blood lactate, hepatic histology and microsomal enzyme activity in non-insulin-dependent diabetics.

The relationship between blood lactate levels, liver histology and microsomal enzyme activity (cytochrome P-450 content) was assessed in 32 non-insulin-dependent diabetics (NIDD) undergoing diagnostic liver biopsy. Fasting blood lactate was related to liver histology and the mean was in the low normal range in the diabetics with an intact liver, whereas higher values were noted in the diabetics with a fatty liver, inflammatory changes and an increase in fibrous trabeculae. Similarly, in the diabetics with an abnormal liver, there was a tendency for pyruvate to be elevated, and body weights and serum insulin concentrations were higher than in the NIDD with an intact liver. P-450 was inversely related to liver histology and its content was reduced in association with increases in fat and fibrous tissues. P-450 was significantly correlated with lactate (rs -0.79), pyruvate (rs -0.65) and serum insulin (rs -0.53). The results revealed close associations between blood lactate, hepatic structure and microsomal enzyme activity, and emphasize that liver function is an important consideration when lactate metabolism is evaluated in NIDD.

Plasma high-density lipoproteins and liver lipids and proteins in man. Relation to hepatic histology and microsomal enzyme induction.

The association of high-density lipoproteins (HDL) in plasma with liver lipids and proteins was investigated in 28 subjects with diagnostic liver biopsy. Lipids and proteins were evaluated in relation to hepatic histology and microsomal enzyme induction, assessed by liver cytochrome P-450. Moderate-severe hepatic parenchymal changes were associated with low liver phospholipids, protein and cytochrome P-450, low plasma HDL cholesterol (HDL-C), and high hepatic triglycerides. Liver microsomal induction accompanying anticonvulsant therapy was associated with high liver phospholipids and protein, high plasma HDL-C, apoproteins A-I and A-II, and high HDL-C/total cholesterol (T-C) ratio. HDL-C, A-I and the HDL-C/T-C ratio were directly proportional to liver phospholipids, protein and cytochrome P-450, inversely related to hepatic triglycerides. Increases in hepatic phospholipids and protein, characteristic of microsomal induction, may lead to the elevation of plasma HDL apoprotein and HDL-C levels and HDL-C/T-C ratios, and thus reduce the risk of coronary heart disease.

Liver damage in nurses handling cytostatic agents.

Three consecutive head nurses developed liver injury after years of handling cytostatic drugs. They had neurological symptoms associated with elevated serum alanine amino-transferase (ALAT) and alkaline phosphatase (ALP) levels. Liver histology showed portal hepatitis with piecemeal necrosis in one of them, the others had hepatic fibrosis and fat accumulation. The subjects' livers were metabolically active as reflected by adaptive and toxic changes in cellular ultrastructure. After withdrawal of the drugs, serum ALAT and ALP values fluctuated between normal and 2-3 times elevated. Follow-up biopsies demonstrated an increase in collagen fibres and a decrease in microsomal enzyme activity, as reflected by arylhydrocarbon hydroxylase activity in vitro. The findings suggest that handling of cytostatic drugs may insidiously damage the liver, which, with time, seems to lead to irreversible fibrosis.

High-density lipoproteins and hepatic microsomal enzyme induction in alcohol consumers.

Plasma HDL cholesterol (HDL-C) and major apolipoproteins, A-I (A-I) and A-II (A-II), and indices of hepatic microsomal function, liver cytochrome P-450 (P-450) and plasma antipyrine clearance rate (AP-CL), in eight alcohol consumers and eight non-drinkers were compared. Alcohol consumers had increased P-450 and AP-CL showing an induction of hepatic microsomal function, and elevated HDL-C, A-I and A-II as compared with values in non-drinkers. Liver cytochrome P-450 concentrations were directly proportional to plasma HDL-C (r = 0.732, p less than 0.01) and A-I (r = 0.564, p less than 0.05) levels. These data suggest that alcohol by inducing liver microsomal function increases plasma HDL and thus favorably alters one of the risk factors of coronary heart disease.

Liver injury in subjects occupationally exposed to chemicals in low doses.

The hepatic injury developing during occupational exposure to chemicals was investigated in 23 male patients, aged 23-49 years, by comparing case histories, liver function tests, hepatic microsomal enzyme activities in vivo and in vitro with histology. The subjects, 15 chemical industry workers and 8 painters, had disturbed liver tests after years of exposure to solvents, paints and lacquers. Characteristic for the patients was a 2-4-fold increase in serum aminotransferases associated with normal liver or reactive hepatitis with or without fatty liver. All patients, except subjects with fatty change, had metabolically active liver which was reflected as adaptive and toxic changes in cellular ultrastructure. The biochemical liver tests normalized within 3-6 weeks after cessation of the exposure. The findings demonstrate that occupational exposure to chemical solvents may insidiously damage the liver. The injury is detectable by biochemical, metabolic and histological investigations in the early phase.

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants.

Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater inthe epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.

Plasma high-density lipoproteins and hepatic microsomal enzyme induction. Relation to histological changes in the liver.

The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal live. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HLD. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.

Treatment of alcoholic cirrhosis with enzyme inducers.

The efficacy of hepatic enzyme-inducing drugs in improving liver function and drug metabolism was investigated in 18 chronic alcoholics with cirrhosis. Five subjects treated continuously with the inducing drugs, phenytoin or prednisolone, for concomitant diseases showed more rapid metabolism than the other patients. Phenobarbital (PB) and medroxyprogesterone acetate (MPA), both known inducers, improved drug metabolism in patients with normal or decreased serum albumin. Serum albumin levels rose in alcoholics with low pretherapy levels, whereas serum albumin in subjects with normal pretherapy levels did not change. Serum thrombotest levels rose in six of seven subjects with low pretreatment values. There was a trend toward normal conventional liver tests during the experiment. There was a relationship between in vivo and in vitro drug metabolism in the alcoholics with cirrhosis. Our results demonstrate that by activating liver function, enzyme-inducing drugs may be of therapeutic value in alcoholics with liver cirrhosis and hepatic failure.

The evaluation of the drug-metabolizing capacity in patients with diabetes mellitus.

Hepatic drug-metabolizing capacity was investigated in 56 diabetics. The antipyrine test was selected as an in vivo index, since its kinetics indirectly reflect the metabolically active liver mass. Hepatic cytochrome P-450 (P-450), determined from the biopsy samples, was used as an in vitro parameter, since it is a direct measure of microsomal drug-metabolizing enzyme activity. There was a wide interindividual variation in the indexes of drug metabolism in the diabetics: 40 fold in P-450 content and eightfold in antipyrine metabolism. P-450 levels were higher and antipyrine metabolism faster in the subjects with normal liver than in those with fatty liver, parenchymal inflammatory changes, or cirrhosis. Thus the in vivo and in vitro parameters of drug metabolism were related to the alterations in liver histology. On the other hand, the diabetes per se did not seem to alter the drug-metabolizing capacity of the liver. Also, drug metabolism in diabetics classified by treatment regimen did not differ significantly.

Plasma high-density lipoprotein cholesterol and hepatic cytochrome P-450 concentrations in epileptics undergoing anticonvulsant treatment.

Relation of plasma high-density lipoprotein (HDL) cholesterol concentration to hepatic microsomal enzyme activity in eighteen epileptics with diagnostic liver biopsy was investigated, the cytochrome P-450 content in biopsy samples being used to reflect the liver enzyme activity. A significant correlation (r = 0.67, P less than 0.01) was found. Combination therapy with anticonvulsants was associated with higher plasma HDL cholesterol and hepatic cytochrome P-450 concentrations than the treatment with phenytoin alone. Serum triglyceride level was inversely related to the hepatic cytochrome P-450 content (r = 0.62, P less than 0.01). Plasma HDL cholesterol and hepatic cytochrome P-450 were related to liver histology. Patients with hepatic fatty infiltration had low HDL cholesterol and cytochrome P-450 concentrations.

Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.

1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P-450) indices of the activity of the hepatic mixed function oxidase system. 3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.