P. V. Luoma

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

Abstract. 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.

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.

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

SummarySerum 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 anti-convulsants, 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 High-Density Lipoprotein Cholesterol in Epileptics Treated with Various Anticonvulsants

Plasma high-density lipoprotein (HDL) cholesterol in 97 epileptics on long-term anticonvulsant therapy was investigated. Therapy with phenytoin alone or in combination with carbamazepine or phenobarbital was associated with elevated plasma HDL cholesterol levels as compared with controls. HDL cholesterol in patients treated with carbamazepine did not diverge from control values. Patients treated with phenytoin and phenobarbital in combination showed higher HDL cholesterol levels than those treated with phenytoin alone. There was an inverse correlation between the HDL cholesterol and serum triglyceride levels. The results demonstrate that high plasma HDL cholesterol might be associated with therapy involving some anticonvulsants known to be potent enzyme inducers. This suggests that the elevation of HDL cholesterol during therapy is probably related to the drug-caused enzyme induction phenomenon.

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.

Plasma high-density lipoproteins and hepatic microsomal enzyme induction

SummaryThe 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 liver. 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 HDL. 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.

Relationship Between Lipid Composition and Drug Metabolizing Capacity of Human Liver

SummaryThe 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 (Pearsonss 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.

Efficacy of Intravenous Disopyramide in the Termination of Supraventricular Arrhythmias

C ARDIAC arrhythmias often constitute a very important therapeutic problem that must be treated effectively. This is particularly so in patients with coronary heart disease where arrhyth.mias have been implicated as the major cause of death.1’2 During the last years very few antiarrhythmic drugs have been introduced, and many common antiarrhythmic agents may have unfavorable side effects. Therefore, it is of prime importance to develop effective and safe drugs for the treatment of disturbances in cardiac rhythm. Disopyramide [4 diisopropylamino -2phenyl 2 (2 pyridyl)butyramide phosphate] is an antiarrhythmic agent which is structurally unrelated to any of the conventional antiarrhythmic compounds.

Serum selenium, glutathione peroxidase, lipids, and human liver microsomal enzyme activity

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.