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.

Decreased serum selenium in alcoholics as related to liver structure and function.

Serum selenium was evaluated in relation to hepatic structure and function in 46 alcoholics with diagnostic liver biopsy classified into 4 groups by hepatic histology. Their serum selenium concentration varied from 12 to 88 micrograms/l and was lower (p less than 0.001) in all groups of alcoholics, ie patients with normal liver (53.0 +/- 20.7 micrograms/l, mean +/- SD), fatty liver (55.8 +/- 21.2 micrograms/l), alcoholic hepatitis (46.0 +/- 14.1 micrograms/l), and cirrhosis (41.1 +/- 12.8 micrograms/l), than in 25 healthy controls (88.7 +/- 11.0 micrograms/l). Serum selenium level was related to the severity of liver disease, and most reduced in subjects with decompensated alcoholic cirrhosis. Their serum selenium level (29.2 +/- 13.7 micrograms/l) was below (p less than 0.05) that obtained in alcoholics with normal liver and fatty liver respectively. Both inadequate dietary selenium intake and alcohol-induced changes in hepatic structure and function may have contributed to the decrease of serum selenium in the subjects studied.

Association of blood cadmium to the area of residence and hypertensive disease in Arctic Finland.

The association of cadmium exposure with area of residence, blood pressure, and arterial hypertensive disease was examined in 230 reindeer herders in northernmost arctic Finland. Blood cadmium concentration averaged 10.0 nmol/l, and was three times higher in smokers than in nonsmokers (16.7 vs. 5.5 nmol/l). Concentrations increased from the southwestern to the northeastern area west of the Kola Peninsula, Russia, both in nonsmokers (3.1 vs. 6.8 nmol/l) and smokers (10.8 vs. 32.0 nmol/l). High cadmium levels were most common in the northeast: 32% of the values were at least 15 nmol/l, 10% at least 45 nmol/l (health-based limit of WHO), and 3% at least 90 nmol/l (the critical limit for renal damage). High cadmium concentration was associated with a rise in blood pressure; the rise was particularly pronounced in subjects with hypertensive diseases. These associations were not affected by age, body mass index, smoking, and alcohol consumption. The results suggest that cadmium exposure may have harmful health effects in arctic Finland and emphasize the importance of reducing pollution from industrial sources in the Kola Peninsula.

Changes in thyroid function tests during phenobarbital treatment in late pregnancy.

The effect of phenobarbital treatment in late pregnancy on thyroid function tests was investigated in 16 women. Ten women in late pregnancy served as controls. Phenobarbital treatment for two weeks was associated with a significant decrease in serum thyroxine (T4) level and in the free thyroxine index (T3U x T4) of 18% and 16%, respectively. These changes were associated with a significant increase in serum thyrotropin concentration of 15%. gamma-Glutamyl transpeptidase activity increased, and serum bilirubin concentration decreased during phenobarbital treatment. The changes in the thyroid function test might reflect the effect of phenobarbital on thyroid hormone metabolism. The changes may have diagnostic importance in borderline cases of thyroid disease.

Serum selenium, glutathione peroxidase, lipids, and human liver microsomal enzyme activity : A double-blind controlled trial of selenium supplementation.

This study evaluated selenium status in relation to lipid peroxidation, liver microsomal function, and serum lipids in humans. Serum selenium concentration, glutathione peroxidase (GSH-Px) activity, liver microsomal enzyme activity, assessed by plasma antipyrine clearance (AP-CL) rate, and serum lipids were determined in 23 healthy subjects in a double-blind placebo-controlled trial of selenium supplementation. The low selenium concentration (74.0±14.2 µg/L, mean±SD) is attributable to the low selenium content of the diet. Subjects with the lowest selenium levels (n=11) had reduced serum GSH-Px activity, AP-CL rate, high-density lipoprotein cholesterol (HDL-C), and total cholesterol (T-C) as compared with subjects with higher selenium concentrations (n=12). Low AP-CL rates were associated with low HDL-C: T-C ratios. Selenium supplementation, 96 µg/d for 2 wk, increased serum selenium, GSH-Px activity, and the HDL-C: T-C ratio. The results suggest that a low serum selenium level is associated with a decrease in liver microsomal enzyme activity and serum HDL-C and T-C concentrations. Selenium supplementation in subjects with low serum selenium may favorably influence relations between serum lipoproteins connected with the development of atherosclerotic vascular disease.

Saliva and plasma clearance of antipyrine as reflectors of liver function.

Antipyrine kinetics, after oral administration to patients with changes in liver function were determined from data obtained by measuring drug concentration in saliva and plasma. Antipyrine kinetics calculated from saliva concentrations did not diverge from values obtained from plasma antipyrine measurements. The saliva and plasma clearance rates were reduced in parallel in subjects with liver parenchymal disease, and showed similar increases in subjects with normal liver treated with enzyme inducing drugs as compared to values in subjects with normal liver and no inducing treatment. The clearance values were related to changes in liver histology. The area under the concentration/time curve was increased in subjects with altered liver histology, and reduced in subjects with normal liver and therapy with enzyme inducing drugs. Antipyrine saliva clearance seems to be a useful method for assessing hepatic drug metabolism and liver microsomal function in vivo in subjects with varying degrees of liver function damage.

Gene-activation mechanisms in the regression of atherosclerosis, elimination of diabetes type 2, and prevention of dementia.

Atherosclerotic vascular disease, diabetes mellitus (DM) and dementia are major global health problems. Both endogenous and exogenous factors activate genes functioning in biological processes. This review article focuses on gene-activation mechanisms that regress atherosclerosis, eliminate DM type 2 (DM2), and prevent cognitive decline and dementia. Gene-activating compounds upregulating functions of liver endoplasmic reticulum (ER) and affecting lipid and protein metabolism, increase ER size through membrane synthesis, and produce an antiatherogenic plasma lipoprotein profile. Numerous gene-activators regress atherosclerosis and reduce the occurrence of atherosclerotic disease. The gene-activators increase glucose disposal rate and insulin sensitivity and, by restoring normal glucose and insulin levels, remove metabolic syndrome and DM2. Patients with DM2 show an improvement of plasma lipoprotein profile and glucose tolerance together with increase in liver phospholipid (PL) and cytochrome (CYP) P450. The gene-activating compounds induce hepatic protein and PL synthesis, and upregulate enzymes including CYPs and glucokinase, nuclear receptors, apolipoproteins and ABC (ATP-binding cassette) transporters. They induce reparation of ER structures and eliminate consequences of ER stress. Healthy living habits activate mechanisms that maintain high levels of HDL and apolipoprotein AI, promote health, and prevent cognitive decline and dementia. Agonists of liver X receptor (LXR) reduce amyloid in brain plaques and improve cognitive performance in mouse models of Alzheimer's disease. The gene activation increases the capacity to withstand cellular stress and to repair cellular damage and increases life span. Life free of major health problems and in good cognitive health promotes well-being and living a long and active life.

Microsomal enzyme induction, lipoproteins and atherosclerosis.

The liver is the principal site for the synthesis and elimination of lipoproteins circulating in plasma, and alterations in hepatic function influence plasma lipoprotein levels. High HDL-C/T-C and apo A-I/apo B ratios, which are characteristic of a low coronary risk, have been typical of healthy subjects with high microsomal enzyme activity in the liver. Microsomal enzyme inducing drugs such as phenytoin, phenobarbital and carbamazepine, and also alcohol, influence serum lipid and apoprotein concentrations. The inducers increase the concentrations of hepatic microsomal enzyme and apo A-I mRNA, and also proteins and phospholipids. They similarly increase serum HDL-C and apo A-I levels and the HDL-C/LDL-C ratio, powerful protective factors against coronary heart disease. These parameters parallel hepatic protein and phospholipid concentrations, and microsomal enzyme activity as assessed by liver cytochrome P-450 or antipyrine kinetics. Serum LDL-C levels are inversely proportional to hepatic cytochrome P-450 concentrations. Experimental studies indicate that phenobarbital retards cholesterol accumulation in the arterial wall and the formation of atherosclerotic plaque. A decreased mortality rate from coronary heart disease has been reported for subjects who take enzyme inducers, drugs or alcohol, whereas impairment of hepatic microsomal function may promote atherogenesis. In addition to drugs non-pharmacological factors such as dietary constituents and physical exercise may influence hepatic microsomal function and hence improve the serum lipoprotein profile. These observations, which connect microsomal inducers, liver lipids and proteins, serum lipids and apoproteins characteristic of a low risk of atherosclerotic disease and low incidence of coronary deaths, lead to the conclusion that the activation of liver microsomal function can prevent atherogenesis in man.

Gene activation, apolipoprotein A-I/high density lipoprotein, atherosclerosis prevention and longevity.

Recent studies in man and human apolipoprotein A-I transgenic animals emphasize the significance of apolipoprotein A-I and high density lipoprotein in antiatherogenesis. Several drugs and other compounds, e.g. phenobarbital, gemfibrozil, fenofibrate, prednisone, estrogen and alcohol, induce apolipoprotein A-I synthesis. They commonly produce serum lipoprotein patterns typical of a low risk of coronary heart disease, and many of them have been found to prevent atherogenesis, reduce coronary heart disease mortality and increase survival. These compounds act against atherosclerosis by using one or several mechanisms that include overexpression of the apolipoprotein A-I gene with an increase in serum apolipoprotein A-I and high density lipoprotein and promotion of reverse cholesterol transport, upregulation of the low density lipoprotein receptor gene with a decrease in serum apolipoprotein B and low density lipoprotein, maintenance of endothelial cell function and protection against thrombosis. They have been found to raise high density lipoprotein cholesterol and apolipoprotein A-I together with a decrease in cholesterol ester transfer protein activity, and to induce hepatic cholesterol 7 alpha-hydroxylase and cholesterol and bile acid elimination from the body. By raising the activities of apolipoprotein A-I/high density lipoprotein-associated paraoxonase and other antioxidative enzymes, the inducers have the capacity to prevent atherogenesis in arterial walls through inhibition of the oxidative modification of low density lipoprotein. Other antiatherogenic vascular actions of high density lipoprotein include interference with low density lipoprotein aggregation and uptake by endothelial cells, and competition with low density lipoprotein for endothelial-localized low density lipoprotein receptors. Apolipoprotein A-I/high density lipoprotein beneficially enhances fibrinolysis, decreases platelet aggregation, increases prostacyclin production and stabilization and prevents atherogenic immune and inflammatory responses. This gene activation or microsomal induction can prevent atherosclerosis and is a basis for tailoring effective new agents and optimal non-invasive therapy against atherosclerotic vascular disease to promote health and enhance longevity.

Lysosomal enzymes in hepatic injury induced by bromobenzene.

In studies with bromobenzene we found increases in the activities of hepatic lysosomal enzymes. The present study was undertaken to determine how these changes are related to the development of hepatic injury after bromobenzene administration. A single intraperitoneal injection of bromobenzene (5 mmoles/kg) caused significant increases in the total activity of lysosomal N-acetyl-beta-glucosaminidase and beta-glucuronidase in rat liver within 8-12 h, whereas it did not alter the free activity of these enzymes. Enhancement of bromobenzene hepatotoxicity by the pretreatment of rats with phenobarbital was not associated with further changes in hepatic N-acetyl-beta-glucosaminidase or beta-glucuronidase activities. Cycloheximide administered prior to bromobenzene inhibited significantly the effect of bromobenzene on the total N-acetyl-beta-glucosaminidase activity. The results suggest that lysosomal enzymes are not directly involved in hepatic damage caused by bromobenzene and that the inhibition of protein synthesis may reduce this response to hepatotoxin.

The effects of phenobarbital on serum high density lipoprotein subfractions and apolipoproteins.

Prospective studies report that a pharmacologic elevation of serum high density lipoprotein (HDL) concentration may be of value in the prevention of atherosclerosis. In this study phenobarbital, 50 mg at bedtime for ten days, increased serum HDL cholesterol, HDL2 cholesterol and HDL cholesterol/cholesterol and HDL cholesterol/apolipoprotein A-I ratios. Phenobarbital treated subjects had serum lipoprotein profile typical of low risk of ischemic heart disease.

The effect of phenobarbital on serum hormone levels and their diurnal variations in pregnancy.

The effect of phenobarbital (PB) on serum hormones in late pregnancy was investigated. 18 pregnant women were studied before and after 2 weeks of PB treatment (100 mg per os, daily at 8 p.m.) by measuring serum estradiol, estriol, progesterone, testosterone, prolactin and cortisol concentrations. 7 pregnant women without PB therapy served as controls. Estradiol levels in the morning decreased, whereas those of estriol increased both in the morning and evening during PB treatment. The estriol/estradiol ratio increased in women on PB. PB affected the diurnal variation of hormones; the decrease in estradiol concentration between 8 a.m. and 8 p.m. was eliminated and the decrease in estriol concentration became more clear. PB did not significantly affect the serum levels of the other hormones investigated. As an enzyme-inducer PB may affect the fate of sex hormones.

Changes in serum triglyceride and cholesterol levels during long-term phenytoin treatment for epilepsy.

The effect of long-term phenytoin therapy on serum triglyceride and cholesterol levels in 20 patients with epilepsy was investigated. In patients followed up for six years, phenytoin treatment was associated with an increase in serum triglyceride and cholesterol levels. The most significant increases in lipid levels were measured during the first months of therapy, whereafter values generally tended to decrease. The elevation in serum triglyceride concentration was relatively greater than that in serum cholesterol level. Cholesterol concentrations, however, remained high for a longer period. The results demonstrate that phenytoin therapy for epilepsy is associated with a rise in serum triglyceride and cholesterol levels, the degree of which seems to be related to the duration of the treatment. The changes presumably reflect phenytoin effects on hepatic lipid metabolism.

Low high-density lipoprotein and reduced antipyrine metabolism in members of a family with polycystic liver disease.

A family with polycystic liver disease was investigated in order to evaluate the role of the liver in determining the serum high-density lipoprotein (HDL) level and its relationship to the rate of antipyrine elimination from plasma. The four subjects with polycystic liver disease had low serum HDL cholesterol, total cholesterol, and apoprotein A-II levels as compared with others in the family. There was an inverse relationship between HDL cholesterol and apoproteins and the antipyrine half-life in plasma. The results demonstrate that serum HDL levels and the antipyrine metabolism, both reflectors of hepatic function, might be altered in parallel in subjects with polycystic liver. The findings presumably reflect the effects of cysts on liver parenchyma and changes in the hepatic blood flow.

High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in northern Finland.

OBJECTIVES: The mortality from coronary heart disease (CHD) is exceptionally low in northernmost Finland, the Sámi (formerly known as Lapp) area. To clarify the reasons for this, the levels of serum cholesterol, other classic risk factors, and major antioxidants, alpha-tocopherol, retinol, albumin and selenium were determined in males living in the low-mortality area and in a reference area. DESIGN: A health survey amongst reindeer herdsmen living in the three northernmost communes of Finland (the Sámi area) and in the six neighbouring communities to the south (the reference area). The mortality from CHD in the two areas was determined from death certificates issued during the period 1981-1990. SUBJECTS: A total of 350 participants of the health survey, mean age 46 (SD 14) years. RESULTS: The mortality from CHD was 17% lower in the Sámi area than in the reference area [95% confidence interval (CI) for the difference: 4-29]. Subjects living in the low-mortality area showed higher serum-lipid-adjusted alpha-tocopherol (18.4 vs. 16.1 mumol L-1; 95% CI for difference: 0.7-3.9; P < 0.001), albumin (46.9 vs. 46.2 g L-1; 0.2-1.3; P < 0.02), selenium (1.59 vs. 1.47 mumol L-1; 0.02-0.22; P < 0.02), cholesterol (6.76 vs. 6.34 mmol L-1; 0.12-0.72; P < 0.001) and LDL cholesterol (4.76 vs. 4.45 mmol L-1; 0.05-0.57; P < 0.02) than those in the reference area. The HDL cholesterol:cholesterol ratio was lower in the Sámi area than in the reference area (0.20 vs. 0.21; -0.02-0.00; P < 0.04). The Sámis showed higher serum selenium than the Finns. Serum alpha-tocopherol increased with the consumption of reindeer meat and serum selenium increased with fish consumption. CONCLUSIONS: Alpha-tocopherol, albumin and selenium may play a role in the low mortality from CHD observed in northernmost Finland. The favourable serum antioxidant status in northerners may be credited to the local diet.

Relationship between plasma high-density lipoprotein cholesterol and anticonvulsant levels in epileptics.

Plasma high-density lipoprotein (HDL) cholesterol is a recognized negative risk factor for coronary heart disease. In this study, therapy with phenytoin alone, carbamazepine alone, and phenytoin in combination with phenobarbital was associated with elevated plasma HDL cholesterol concentrations. The highest HDL cholesterol levels were seen in subjects treated with the combination of phenytoin and phenobarbital. Plasma HDL cholesterol levels were proportional to the serum phenobarbital and carbamazepine concentrations. In subjects treated with phenytoin alone, low plasma HDL cholesterol levels were associated with low drug concentrations. The results suggest direct links running from the serum anticonvulsant levels to the extent of hepatic microsomal enzyme induction, and further to the plasma HDL cholesterol concentrations.

Phenobarbital pharmacokinetics and salivary and serum concentrations in pregnancy.

The pharmacokinetics and the ratio between salivary and serum concentrations of phenobarbital (PB) were determined in 10 women undergoing treatment in late pregnancy. An approximately 2.5-fold variation was measured in the apparent relative clearance rates of PB in the women studied. The means of the total clearance rate (0.255 L/h), the relative clearance rate (4.0 ml/h/kg of body weight), the elimination half-life (95 h), the elimination rate constant (0.0071/h), and the apparent volume of distribution (35.49 L) were within the ranges observed in nonpregnant subjects. The PB concentration in saliva was 34% of that in serum. Salivary and serum levels of PB correlated closely with each other. Serum gamma-glutamyl transpeptidase activity increased, and total bilirubin concentrations decreased during PB treatment, both of which can be linked to the PB-caused hepatic microsomal enzyme induction phenomenon. The variation in clearance rate emphasizes the importance of close monitoring of PB treatment of pregnant women. The results suggest that salivary PB measurements can be used with sufficient accuracy to predict PB concentrations in the serum and to optimize PB treatment during pregnancy.

Serum LDL cholesterol, the LDL/HDL cholesterol ratio and liver microsomal enzyme induction evaluated by antipyrine kinetics.

The association of serum LDL and HDL cholesterol with hepatic microsomal enzyme induction, assessed by plasma antipyrine kinetics was investigated in 30 epileptics. Patients on enzyme-inducing anticonvulsants had reduced LDL/HDL cholesterol ratios and elevated HDL cholesterol concentrations and HDL/total cholesterol ratios, indicating a cholesterol transfer from LDL to HDL. Strong hepatic microsomal enzyme induction was associated with reduced LDL cholesterol. The LDL/HDL cholesterol ratio was negatively proportional and the HDL/total cholesterol ratio positively proportional to the antipyrine clearance rate. Epileptics, particularly those with a high antipyrine clearance, had a cholesterol distribution pattern characteristic of a low probability of developing coronary atherosclerosis. The results support the view that hepatic microsomal enzyme induction favourably alters the cholesterol distribution in the body.