Biomedical subjects

A J Arranto

Publications and source records attributed to A J Arranto.

At least 19 recordsLinked to original sources

PubMed1997

Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions.

OBJECTIVES: The effect of aging on drug metabolism in humans has not yet been completely described. METHODS: Two hundred twenty-six patients with equal histopathologic conditions were investigated. The cytochrome P450 contents in the liver biopsy samples, the plasma antipyrine clearance rates after oral administration and, as an independent control of vitality, serum testosterone levels were determined. RESULTS: Cytochrome P450 content in subjects from 20 to 29 years of age was 7.2 +/- 2.6 nmol.gm-1, increased during the fourth decade (+7.2%, p = NS), declined after 40 years (-16%, p < 0.01) to a level that remained unaltered up to 69 years, and declined further after 70 years (-32%, p < 0.001). The antipyrine (phenazone) clearance rate in young subjects was 46.4 +/- 18.5 ml.min-1, remained unaltered during the fourth decade, and declined after 40 years by a rate of 0.34 ml.min-1 per year toward old age (-29%, p < 0.001). The half-life in young subjects was 9.5 +/- 2.0 hours and increased after 30 years toward old age (+26%, p < 0.001). The volume of antipyrine distribution, 0.46 +/- 0.12 L.kg-1 in young subjects, decreased after 30 years (-11%). In line with the testosterone content, the decrease in drug metabolism was equal in both sexes. CONCLUSION: This study shows a reduction of in vitro and in vivo drug metabolism with age in humans. The data suggest that at least three age groups--young, middle-aged, and elderly--should be included in the evaluation of the pharmacokinetics of a new drug. The reduction of drug metabolism (-30%) after 70 years of age indicates that care is needed in the prescription of drugs for elderly subjects.

Adult↗

PubMed1986

Insulin-mediated glucose metabolism is related to liver structure and microsomal function.

The role of the liver in glucose metabolism was investigated in 24 consecutive patients undergoing diagnostic liver biopsy by comparing hepatic morphometry and microsomal enzyme activity in vivo (antipyrine) with fasting blood glucose (BG) and immunoreactive insulin (IRI) levels and with the metabolic clearance rate of insulin and the insulin sensitivity index. The patients had elevated BG and IRI levels and reduced insulin-mediated glucose metabolism, insulin sensitivity index, and microsomal enzyme activity as compared with controls. The insulin metabolic clearance rate did not diverge among the groups. Patients with fatty liver had a high BG associated with a reduced glucose disposal rate, whereas fasting IRI did not diverge when compared with other liver patients. Glucose disposal rate was related to the amount of unaltered liver (r2 = 0.640; p less than 0.001) and antipyrine metabolism (r = 0.631; p less than 0.01) and inversely related to the amount of fat (r2 = 0.585; p less than 0.01). The findings demonstrate that insulin-mediated glucose metabolism is related to liver structure and microsomal function. Accumulation of fat in the liver seems to be a major factor associated with reduced insulin sensitivity and glucose tolerance.

Alanine Transaminase↗

PubMed1986

Polyamine biosynthesis and monooxygenase enzyme activity in rat liver cirrhosis and regeneration.

Chemically induced liver cirrhosis in the rat was associated with an increased biosynthesis of the hepatic polyamines putrescine and spermidine and a reduction in the activities of the cytochrome P-450-associated monooxygenase enzymes aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. These parameters were normalized after a 4-week spontaneous regeneration period. The results suggest an independent regulatory mechanism of polyamine biosynthesis and monooxygenase expression.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1985

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.

Adult↗

PubMed1985

Carbohydrate intolerance associated with reduced hepatic glucose phosphorylating and releasing enzyme activities and peripheral insulin resistance in alcoholics with liver cirrhosis.

Carbohydrate intolerance was investigated in 8 alcoholics with liver cirrhosis and in controls. Indices of carbohydrate metabolism, glucose and insulin levels after glucose loading, were compared with glucose phosphorylating (glucokinase, hexokinase) and releasing (glucose-6-phosphatase) enzymes. Comparison was also made with pericellular collagen in liver biopsies and with insulin sensitivity assessed by the euglycemic clamp technique and with conventional liver function tests including oral antipyrine test. Glucokinase activity was low or absent, hexokinase activity increased and the GK/HK ratio reduced. Glucose-6-phosphatase activity was lowered and insulin sensitivity decreased. Pericellular collagen was increased (P less than 0.001) and related to the fasting glucose (r0.593) and insulin levels (r0.526). Blood glucose was related to antipyrine metabolism (r-0.727) but not to the other liver tests. Glucose intolerance in cirrhosis seems to be associated with reduced glucose phosphorylating and liberating enzyme activities. Hyperinsulinaemia, developing secondarily, may then lead to insulin resistance.

Adult↗

PubMed1985

Treatment of liver cirrhosis with microsomal enzyme-inducing compound in the rat.

The effect of therapy with a microsomal enzyme-inducing drug on the cirrhotic liver in male Wistar rats was investigated by morphological and biochemical means. The cirrhotic animals were treated with medroxyprogesterone acetate (MPA) 100 mg/kg body wt, i.p. daily for a week. In the cirrhotic rats liver weight was enhanced, liver protein content was increased while total liver DNA content remained unchanged upon MPA treatment. The hepatic regenerative nodule size increased, as determined by morphological means. Hepatic microsomal metabolic activity was improved, as seen by increases in NADPH-cytochrome P-450 reductase and aminopyrine N-demethylase activities and cytochrome P-450 content. Since the increases in liver protein content and metabolic activity were relatively greater in the cirrhotic than intact animals upon MPA treatment, it was suggested that the spontaneous regeneration associated with liver cirrhosis may affect the induction phenomenon. The results demonstrate that an enzyme inducer may have beneficial effects on the cirrhotic liver by elevating metabolic activity and parenchymal mass.

Aminopyrine N-Demethylase↗

PubMed1985

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.

Adult↗

PubMed1985

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.

Blood Glucose↗

PubMed1985

Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects.

The reduction in blood glucose in non-insulin-dependent diabetes mellitus (NIDDM) brought about by the use of phenobarbital (PB), a hepatic microsomal enzyme inducer, suggests an improvement in insulin sensitivity. The effect of PB on insulin-mediated glucose metabolism was hence investigated using the euglycemic clamp technique in 10 women with NIDDM aged 56-75 yr. The addition of PB to sulfonylurea therapy, concurrently for 6 wk, reduced fasting blood glucose (BG, from 12.8 +/- 1.6 to 10.2 +/- 3.2 mmol/L, P less than 0.01) and immunoreactive insulin (IRI) levels (from 32.4 +/- 13.6 to 24.7 +/- 9.8 mU/L, P less than 0.01), whereas body weight remained unaltered. During the trial, there was a significant change in the glucose disposal rate (M, from 1.27 +/- 0.60 to 2.82 +/- 0.86 mg/kg/min, P less than 0.001), the metabolic clearance rate of glucose (from 0.89 +/- 0.41 to 2.24 +/- 1.27 ml/kg/min, P less than 0.01), the insulin sensitivity index (from 1.10 +/- 0.44 to 2.86 +/- 1.54 mg/kg/min: mU/L X 100, P less than 0.001), and the plasma antipyrine clearance rate (from 28.3 +/- 11.7 to 51.4 +/- 20.2 ml/min, P less than 0.001), an in vivo index of liver microsomal enzyme activity. The antipyrine clearance rate correlated with insulin-mediated glucose metabolism (r2 = 0.560, P less than 0.01). This correlation could be interpreted as indicating that, in NIDDM patients, peripheral glucose utilization and the liver microsomal enzyme system share common regulators. Our study suggests a new approach to the improvement of insulin sensitivity in NIDDM patients.

Aged↗

PubMed1985

Metabolism of medroxyprogesterone acetate and hepatic drug metabolism activity.

The effect of microsomal enzyme activity on the hepatic metabolism of medroxyprogesterone acetate (MPA), measured in vitro, and the MPA concentrations in liver and plasma were investigated in rats with intact and injured livers before and after MPA therapy. The amount of total MPA metabolites and the activity of drug-metabolizing enzyme system changed in a parallel manner in the livers. The ratio of liver/plasma concentration of MPA was decreased in the liver injury. The hepatic metabolism of MPA is accelerated during MPA treatment in rat.

Animals↗

PubMed1984

Hepatic glucose-6-phosphatase activity in non-insulin dependent diabetics. Effect of enzyme-inducing drugs.

The role of glucose-6-phosphatase (G6Pase) in postreceptional glucose handling in non-insulin dependent diabetics ( NIDDs ) was in investigated by comparing the enzyme values in diagnostic liver biopsy samples with fasting blood glucose (BG), immunoreactive insulin (IRI) and plasma antipyrine half-life (T/2). The NIDDs , treated with sulphonylureas, had elevated serum aminotransferase and alkaline phosphatase values associated with fatty liver with or without fibrosis. G6Pase activity was reduced in the NIDDs compared with subjects who had undergone gallstone surgery (p less than 0.001), insulin dependent diabetics (p less than 0.001), and age- and sex-matched non-diabetics (p less than 0.001). G6Pase was inversely related to BG and antipyrine T/2, but not to IRI or conventional liver function tests. Therapy with phenobarbital and medroxyprogesterone acetate, known inducers, increased G6Pase activity, shortened antipyrine T/2, reduced BG and did not alter IRI, in four NIDDs . Low liver G6Pase activity in NIDDs may hence be one factor underlying the impaired glycemic control.

Aged↗

PubMed1983

Medroxyprogesterone induced changes in rat liver. A light and electron microscopic study.

Medroxyprogesterone acetate (MPA) induced morphological alterations in the normal female rat liver and after carbon tetrachloride exposure were assessed by light and electron microscopy and morphometry. Administration of MPA increased the smooth endoplasmic reticulum (SER) in normal rat. Carbon tetrachloride, injected intraperitoneally for four weeks, caused fatty accumulation, enlargement of the cell nucleus and decrease of the rough endoplasmic reticulum (RER) and increase of the SER. After one week of recovery, without treatment, the fatty infiltration and the SER membranes decreased and the RER increased. MPA, following injury, induced a decrease in the fatty accumulation and mitochondrial volume density and the hepatocyte nuclear and cytoplasm size normalized. The SER membrane volume density increased and the surface density decreased, the RER membrane volume density increased while the surface density did not alter significantly. The volume densities of the mitochondria and the peroxisomes decreased in the MPA treated CCl4 exposed groups. The results demonstrate that MPA induces a proliferation of the SER in normal rat liver and after hepatic injury the compound has a beneficial effect on the regeneration.

Animals↗

PubMed1983

Treatment of noninsulin-dependent diabetes mellitus with enzyme inducers.

Although treated adequately with antidiabetic drugs, diet, exercise, and education, patients with noninsulin-dependent diabetes mellitus (NIDDM) may develop resistance to treatment. In NIDDM hepatic microsomal enzyme activity is reduced and since postreceptional glucose metabolism is influenced by these enzymes, we treated the subjects with enzyme-inducing drugs. These inducers (phenobarbital and medroxyprogesterone acetate) when added as adjuvant therapy to sulfonyl urea regimen, reduced blood glucose and plasma insulin, and increased microsomal enzyme activity (as indicated by increased antipyrine metabolism). A trial with placebo did not alter serum glucose levels. Body weight fell and serum aminotransferase levels were normalized. These changes were reflected by reduction of liver fat content (determined by light microscopy), by increased surface density of smooth endoplasmic reticulum, and by repairation of the plasma cell membrane of hepatocytes, as seen in electron micrographs. Activation of postreceptional events in hepatocytes may thus be a new approach in the treatment of therapy-resistant type II diabetes.

Aged↗

PubMed1983

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.

Adult↗

PubMed1983

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.

Adult↗

PubMed1983

Evaluation of liver steatotic and fibrous content by computerized tomography and ultrasound.

Twenty-four patients with steatotic liver underwent computerized tomography (CT) and ultrasound (US) examinations and liver biopsy, performed within a maximum interval of 6 weeks. The CT and US findings were compared with the fat and fibrous content of the biopsy specimens. A good linear inverse correlation between the CT findings and fat content was found. The ranges of CT values were 39-60 HU (mean, 52 HU) for mild fat content (less than or equal to 9.9%), 4-46 HU (mean, 27 HU) for moderate fat content (10.0-24.9%), and -6 to 19 HU (mean, 10 HU) for severe fat content (greater than or equal to 25.0%). With US it was possible to estimate roughly the fat and fibrous content of the liver. There was always the 'bright liver' finding in patients with 10.0% or more fat content, but it was impossible to estimate the content of fat more accurately. 'Bright liver' was also found in most patients with mildly and in all patients with severely increased fibrous content. It was impossible to differentiate the latter from each other or from the 'bright liver' caused by fatty degeneration.

Adult↗

PubMed1983

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.

Adult↗

PubMed1982

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.

Adult↗