DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene.

Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.

Chromosome 4q locus associated with insulin resistance in Pima Indians. Studies in three European NIDDM populations.

Markers on chromosome 4q have recently been shown to be associated with insulin resistance in Pima Indians, a population in which insulin resistance precedes and predicts the development of non-insulin-dependent diabetes mellitus (NIDDM). To examine whether genes in this region could play a major role in susceptibility to NIDDM in other populations, we have examined the allele frequencies of a trinucleotide repeat near the fatty acid-binding protein 2 (FABP2) gene on 4q28-31 in three European populations: Finnish, U.K. Caucasian, and Welsh. The U.K. NIDDM population was selected for insulin resistance by studying patients whose obesity-corrected fasting plasma insulin before treatment was above the 98th percentile. Seven alleles were detected. On cross-tabulation analysis, there were no significant associations between allele frequencies and glucose intolerance in any of the populations. Log-linear analysis of the results from all three populations suggested a moderately significant interaction of glucose tolerance status (normal versus diabetic) and the FABP2 allele (partial chi 2 = 24, df 6, P = 0.027). The parameter describing the interaction of allele A3 and glucose tolerance status was the only such parameter differing significantly from zero (z-score +2.003, P = 0.046). In both the Finnish and U.K. population, the A3 allele was found approximately twice as frequently in NIDDM than in control subjects (Finnish control subjects, impaired glucose tolerance, and NIDDM: 12.2, 22.4, and 26.6%, respectively; U.K. control subjects and NIDDM: 7.8 and 14.6%, respectively). In the Finnish populations, no associations were found between FABP2 alleles and plasma insulin levels or with homeostatic model assessment (HOMA) estimates of beta-cell function and insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study.

OBJECTIVE: To investigate the role of diet as a predictor of glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: At the 30-year follow-up survey of the Dutch and Finnish cohorts of the Seven Countries Study, in 1989/1990, men were examined according to a standardized protocol including a 2-h oral glucose tolerance test. Information on habitual food consumption was obtained using the cross-check dietary history method. Those 338 men in whom information on habitual diet was also available 20 years earlier were included in this study. Subjects known as having diabetes in 1989/1990 were excluded from the analyses. RESULTS: Adjusting for age and cohort, the intake of total, saturated, and monounsaturated fatty acids and dietary cholesterol 20 years before diagnosis was higher in men with newly diagnosed diabetes in the survey than in men with normal or impaired glucose tolerance. After adjustment for cohort, age, past body mass index, and past energy intake, the past intake of total fat was positively associated with 2-h postload glucose level (P < 0.05). An independent inverse association with the past intake of vitamin C was observed (P < 0.05). These associations were independent of changes in the intake of fat and vitamin C during the 20-year follow-up. An increase in the consumption of vegetables and legumes, potatoes, and fish during the 20-year follow-up was inversely related with 2-h glucose level (P < 0.05). CONCLUSIONS: Although the regression coefficients were in general not very large, these results indicate that a high intake of fat, especially that of saturated fatty acids, contributes to the risk of glucose intolerance and NIDDM. Foods such as fish, potatoes, vegetables, and legumes may have a protective effect. In addition, the observed inverse association between vitamin C and glucose intolerance suggests that antioxidants may also play a role in the development of derangements in glucose metabolism.

Hypertriglyceridemia in different degrees of glucose intolerance in a Finnish population-based study.

OBJECTIVE: To determine the prevalence of hypertriglyceridemia and the mean serum triglyceride concentrations in different degrees of glucose tolerance--non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). In addition, we analyzed the correlates of serum triglyceride concentration to explain why it is more prevalent in diabetic subjects. RESEARCH DESIGN AND METHODS: This study was a cross-sectional survey of 4000 people aged 45-64 yr randomly drawn from the population register of the Finnish population of the provinces of North Karelia and Kuopio in eastern Finland and Turku/Loimaa area in southwestern Finland and stratified by four 10-yr age- and sex groups. The final material comprised 96 subjects with NIDDM, 102 subjects with IGT, and 323 subjects with normal glucose tolerance classified on the basis of two 2-h oral glucose tolerance tests. The prevalence of hypertriglyceridemia by the glucose tolerance status and the variation in serum triglycerides associated with selected life-style and biochemical factors were executed as the main outcome measures. RESULTS: The prevalence of hypertriglyceridemia (greater than or equal to 2.3 mM) was 47.6% (95% confidence interval [CI] 32.5-62.7%) in NIDDM men, 21.9% (95% CI 7.6-36.2%) in IGT men, and 15.4% (95% CI 9.3-21.5%) in NGT. In women, hypertriglyceridemia was found in 51.9% (95% CI 38.6-65.2%) among those with NIDDM, 25.7% (95% CI 15.5-35.9%) among those with IGT, and 10.7% (95% CI 6.3-15.1%) in women with NGT. After adjusting for body mass index (BMI) and age, the difference in the prevalence of hypertriglyceridemia between the glucose tolerance groups remained significant in both men (P = 0.008) and women (P = 0.0001). High serum total cholesterol, high BMI, high waist-hip ratio, and low high-density lipoprotein (HDL) cholesterol were significantly associated with high serum triglycerides in all glucose tolerance groups. No synergistic effect between these parameters and glucose tolerance status was found. In multiple linear regression analyses, fasting plasma insulin, diabetes status, and serum uric acid were significant predictors of serum triglyceride concentration after taking into account age, BMI, and HDL and total cholesterol. The association between BMI and serum triglycerides in the regression analysis was significant only when plasma insulin was not included in the model. CONCLUSIONS: Hypertriglyceridemia is common in subjects with NIDDM and IGT and is often associated with low HDL cholesterol, high total cholesterol, hyperinsulinemia, and elevated serum uric acid concentration.

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.

Propranolol and sotalol metabolism after a drinking party.

The effects of alcohol consumed during an evening party on the metabolism and response of beta-adrenergic blocking drugs were investigated in healthy subjects. The drugs were given 12 hr after the first drink. The plasma clearance rate of propranolol, metabolized in the liver, increased, while that of sotalol, which is eliminated unchanged, was reduced. Plasma propranolol levels, but not those of sotalol, were related to blood alcohol content. The blood pressure-reducing effect of propranolol diminished after alcohol and that of sotalol increased. Both drugs reduced the heart rate after alcohol although they were unable to cancel out entirely the alcohol-induced increase in the heart rate. The results show that drinking may alter the metabolism of beta-blocking drugs. Drinking habits must be considered in therapy with beta-blocking drugs or when seeking reasons for angina pectoris or arterial hypertension that does not respond to therapy.

Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase.

Cytochrome P450 2A6 (CYP2A6) is a polymorphic enzyme responsible for the oxidation of certain precarcinogens and drugs and is the major nicotine C-oxidase. The role of CYP2A6 for nicotine elimination was emphasised recently by the finding that smokers carrying defective CYP2A6 alleles consumed fewer cigarettes [Pianezza et al. (1998) Nature 393, 750]. The method used for CYP2A6 genotyping has, however, been found to give erroneous results with respect to the coumarin hydroxylase phenotype, a probe reaction for the CYP2A6 enzyme. The present study describes an allele-specific PCR genotyping method that identifies the major defective CYP2A6 allele and accurately predicts the phenotype. An allele frequency of 1-3% was observed in Finnish, Spanish, and Swedish populations, much lower than described previously.

Prevalence of coronary heart disease and associated risk factors among elderly Finnish men in the Seven Countries Study.

The prevalence of coronary heart disease (CHD), cardiovascular disease (CVD) and associated risk factors was studied in 413 men aged 70-89, the survivors of the Finnish cohorts of the Seven Countries Study. Men were divided into five categories according to manifestations of prevalent CVD: I, history or ECG evidence of previous myocardial infarction (MI; 48 men, 12%); II, typical angina pectoris (AP; 56 men, 14%); III, other ischaemic electrocardiographic (ECG) changes (82 men, 20%); IV, stroke, transient ischaemic attack, intermittent claudication or minor ECG changes (other CVD; 78 men, 19%); V, free of CVD (149 men, 36%). Both systolic and diastolic blood pressures were lowest in men with previous MI and in men free of CVD, and highest in men with other ischaemic ECG changes (P = 0.017). Low HDL-cholesterol (< 0.9 mmol/l) was more prevalent and the total/HDL-cholesterol ratio and triglyceride levels were higher in men with prevalent CHD (P < 0.05). Total and LDL-cholesterol, smoking, body mass index, fibrinogen, coagulation factor VIIc, apolipoprotein A-I, apolipoprotein B and lipoprotein(a) were not associated with prevalent CVD. The results show that manifestations of CHD and CVD are common among elderly Finnish men. Low HDL-cholesterol, total/HDL ratio, triglycerides and hypertension were associated with manifest CVD cross-sectionally.

Intra- and interindividual variability of hemostatic factors and traditional cardiovascular risk factors in a three-year follow-up.

Elucidation of the key role of thrombosis in cardiovascular disease events has arisen considerable interest in hemostatic factors and in the repeatability of their determinations. Data on long-term repeatability has, however, remained scanty. We examined twice 208 men and 265 women in North Karelia, eastern Finland. The baseline examination was a part of the FINRISK 1992 Hemostasis Study and the age-range of participants was between 45-64 years. The re-examination took place three years later in 1995. Both surveys followed the same protocol and were carried out during the same season. Spearman rank correlation coefficients between 1992 and 1995 measurements of fibrinogen, factor VII coagulant activity (FVII:C), factor VII antigen (FVII:Ag), and plasminogen were among men 0.72, 0.77, 0.46 and 0.56, respectively. For total cholesterol, HDL-cholesterol, triglycerides and diastolic blood pressure the corresponding coefficients were 0.74, 0.83, 0.66, and 0.54. In women, the coefficient of fibrinogen was lower than in men, 0.62, otherwise the results were similar. Of men belonging to the highest quarter of fibrinogen, FVII:C, FVII:Ag and plasminogen in 1992, 65%, 60%, 53% and 60% belonged to the highest quarter of respective distributions also in 1995. In women, the corresponding proportions were 64%, 65%, 46% and 58%. The modest repeatability of FVII:Ag and plasminogen was mainly due to the high intraindividual variability. However, in comparisons of plasma levels between two groups, relatively small sample sizes seemed to give adequate statistical power to detect possible differences in FVII:Ag and plasminogen. In conclusion, the long-term repeatability of fibrinogen and FVII:C is similar to that of triglycerides and even better than that of diastolic blood pressure, but somewhat lower than the repeatability of total cholesterol. FVII:Ag and plasminogen did not have very good repeatability and more than one measurement of them should be considered if they are used as predictors of cardiovascular disease in prospective studies.

Medroxyprogesterone acetate improvement of the hepatic drug-metabolizing enzyme system in rats after chemical liver injury.

Medroxyprogesterone acetate (MPA) has an inducing effect on the hepatic drug-metabolizing enzyme system in the rat. The effect of MPA on the liver metabolism was further evaluated here by investigating the restoration of hepatic function after chemical liver injury in female rats. The hepatic injury was induced by pretreating the animals with CCl4 and dimethylnitrosamine for 4 weeks, after which rats treated with MPA for a week were compared with rats showing spontaneous regeneration upon treatment with the MPA vehicle only. Changes in various parameters of the drug-metabolizing enzyme system were used as indices of hepatic function together with liver protein content. The results showed that MPA therapy increased the cytochrome P-450 content and the activity of NADPH-cytochrome c reductase, the monooxygenase enzymes benzo[a]pyrene hydroxylase and aminopyrine N-demethylase, epoxide hydrolase and glutathione S-transferase. MPA increased the relative values in the rats with liver injury almost equally to, or even more than, that seen in the intact animals in comparison to the corresponding vehicle-treated rats. MPA seemed to enhance protein synthesis during liver regeneration, as indicated by changes in total liver protein and in the gel electrophoresis pattern of the microsomal proteins. The hepatic enzyme induction and enhancement of protein synthesis achieved by MPA after liver injury may be of value in the treatment of liver diseases.

Prevalence of diabetes mellitus and impaired glucose tolerance in the middle-aged population of three areas in Finland.

The prevalence of diabetes mellitus and impaired glucose tolerance (IGT) was determined in a random sample of the population aged 45-64 years in three areas of Finland. The two-hour oral glucose tolerance test was repeated in subjects whose first test suggested abnormal glucose tolerance. In the final classification, based on the results of the two tests, the age-standardized prevalence of diabetes, according to the WHO criteria was 5.7% (95% confidence interval (CI): 4.3-7.1) in men and 4.6% (95% CI: 3.6-5.0) in women. The prevalence of IGT was 3.1% (95% CI: 2.1-4.1) in men and 5.1% (95% CI: 3.9-6.3) in women. Among those aged 55-64 years the prevalence was 6.9% in men and 7.5% in women. The prevalence of diabetes and IGT were not different between the three areas. The age-specific mean values of fasting and two-hour blood concentrations and the 90th percentiles of the blood glucose distributions were also not different between the areas. The prevalence of IGT and diabetes increased with age more steeply among women than men. The median of fasting blood glucose did not change, but the 90th percentile increased with increasing age. The entire distribution of two-hour blood glucose shifted towards higher values with ageing, but the major increase was seen for the 95th percentile. The majority of the diabetic subjects were aware of their condition. The awareness was better among men than women.

Hepatic drug metabolism and the activities of NADPH generating enzymes and glucose-6-phosphatase in phenobarbital treated genetically obese (ob/ob) mice.

We aim to evaluate the effects of phenobarbital (PB) on the liver drug metabolism, NADPH production capacity and terminal gluconeogenic enzyme, glucose-6-phosphatase (G6Pase) activity in the diabetic state associated with genetic obesity in mice. The results showed that PB treatment increased the amount of liver total cytochrome P450 (cytP450), a drug metabolizing monooxygenase enzyme in genetically obese, hyperglycemic (ob/ob) mice 6-fold and the total activities of other monooxygenase enzymes NADPH cytP450 reductase and 7-ethoxyresorufin O-deethylase (ERDE) 2- and 6.5-fold, respectively. In addition, the regimen increased the liver total activities of two NADPH generating enzymes, 6-phosphogluconate dehydrogenase (6PGDH) and malic enzyme (ME) in obese mice suggesting that the regimen enhanced liver NADPH production capacity in the animals. The data further showed that PB treatment decreased the high hepatic G6Pase activity in obese mice. Both enhanced NADPH generating enzyme activities and lowered G6Pase activity may suppress hepatic glucose output. Since NADPH is required for drug oxidation reactions as a reducing cofactor, high NADPH generating capacity may facilitate liver drug metabolism in vivo. Although the diabetic state in obese mice differs somewhat from that seen in non-insulin dependent diabetic subjects (NIDDs), these findings provide some knowledge about the possible biochemical mechanisms whereby PB treatment normalizes drug metabolism and glycemic control in NIDDs, as has been noted in previous studies.

Utility of the Arg/Gln polymorphism of the factor VII (FVII) gene, serum lipid levels and body mass index in the prediction of the FVII:C and FVII:Ag in North Karelia; a cross-sectional and prospective study.

The arginine/glutamine (Arg/Gln) polymorphism of the factor VII (FVII) gene is associated with variation in coagulation activity (FVII:C) and antigen concentration (FVII:Ag) of the FVII protein. We estimated frequency distributions of the Arg and Gln alleles and respective genotypes in North Karelia, and evaluated the utility of this polymorphism, serum lipids, and body mass index (BMI) in the prediction of the distributions of FVII:C and FVII:Ag in a cross-sectional study and in a prospective cohort study. The sample comprised 203 males and 262 females (aged 45-64 years) who were seen twice, in 1992 and 1995. The Arg/Arg genotype and the Arg allele frequencies were among the highest reported so far (86 and 93% respectively, in men; and 89 and 94% respectively, in women). Intragenotypic means of both FVII:C and FVII:Ag were significantly higher in the Arg/Arg genotype than in the Arg/Gln genotype in both genders. Also, intragenotypic variances were different in different genotypes in females. Regression relationships between the FVII:C and FVII:Ag and serum triglyceride, and total cholesterol levels and BMI were positive in both genotypes in both genders, which has not been found in other populations. In prospective analyses, average changes in the FVII:C and FVII:Ag were genotype specific in both genders, as were also regression relationships between these changes and changes in triglyceride level in females (P = 0.065 for FVII:C and P = 0.061 for FVII:Ag). A consequence of these complex genetic architectures is that predictive utility of the Arg/Gln genotypes depends on population, gender, serum lipid levels, and BMI, and changes in these factors over time.

Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region.

OBJECTIVES: To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN: Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. SETTING: Two communities in Finland. SUBJECTS: Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. MAIN OUTCOME MEASURES: Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. RESULTS: Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). CONCLUSIONS: These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.

Variation in 5' promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study.

The objective of this study was to evaluate whether an increased hazard of developing ischemic heart disease (IHD) is associated with any of the three genotypes A560T832/A560T832, A560T832/A560G832 and A560T832/T560T832, defined by variations in two non-coding SNPs in the 5' promoter region of the apolipoprotein E (APOE) gene. These genotypes were selected because they distinguished between high and low levels of HDL-C, TG and/or T-C in our earlier study of multiple samples defined by gender and population. We found a significant increase (p<0.05) in the hazard of IHD in females with the A560T832/T560T832 genotype that remained significant after fitting the effects of dyslipidemia, other established risk factors, and the structural isoform variations of the ApoE molecule. We discuss why this statistically significant genetic predictor may not be an appropriate screening test for IHD in the Danish population at large.

A comparison of the effects of phenobarbital and medroxyprogesterone acetate on drug and glucose metabolism in rats with chemical liver injury.

The effects of medroxyprogesterone acetate (MPA) and phenobarbital (PB) on hepatic glucose and drug metabolism were investigated in male rats after liver injury, induced with dimethylnitrosamine (DMN). MPA normalized fasting blood glucose (BG) and serum immunoreactive insulin (IRI) levels and enhanced hepatic glucose-6-phosphatase (G6Pase) and NADPH cytochrome P450 reductase activities and glycogen and cytochrome P450 (cytP450) contents after liver injury. PB improved hepatic glycogen and cytP450 contents and NADPH cytP450 reductase activity in DMN pretreated rats. The increase in drug metabolism was more pronounced after PB than MPA therapy whereas MPA had more effect on glucose metabolism than had PB. This suggests that the inducing properties of these compounds diverge from each other.

Medroxyprogesterone acetate (MPA) enhances liver NADPH-generating enzyme activities in normal rats.

The aim of the present study was to evaluate the effects of medroxyprogesterone acetate (MPA), an inducer of liver drug metabolism, on the ability of liver to generate NADPH, a reducing cofactor for drug oxidation reactions in normal rats and to compare these results with those obtained in rats receiving phenobarbital (PB), a well known inducer of liver drug metabolism. The results showed that: 1. Administration of MPA (100 mg/kg body wt) for a week increased liver wt and NADPH cytochrome P-450 reductase activity, suggesting that the compound induced liver drug metabolism. 2. The regimen also increased the activities of two NADPH generating enzymes, isocitrate dehydrogenase and malic enzyme, suggesting that MPA enhanced the capacity of normal liver tissue to produce NADPH. 3. Phenobarbital treatment increased the activities of three NADPH generating enzymes, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and malic enzyme, suggesting that MPA and PB differ in their effects on the liver NADPH-producing system.

An ecological study of association between coronary heart disease mortality rates in men and the relative frequencies of common allelic variations in the gene coding for apolipoprotein E.

Three common alleles, epsilon2, epsilon3, and epsilon4, of the gene coding for apolipoprotein E (apoE) have been identified as predictors of interindividual variation in measures of lipid and lipoprotein metabolism, and ultimately risk of coronary heart disease (CHD), within many populations. Here we evaluated the utility of the geographic distribution of these alleles for prediction of interpopulation variation in average level of serum total cholesterol and other traditional risk factors, and CHD mortality rate. We employed published estimates of the relative frequencies of the three common apoE alleles, average levels of risk factors such as serum total cholesterol, systolic and diastolic blood pressure, body mass index, smoking prevalence and CHD mortality rate for nine population-based samples of middle-aged males studied by the international WHO MONICA Project. There was approximately a 10-fold difference between the highest and lowest CHD mortality rate. Of the traditional risk factors, variation in the average level of serum total cholesterol was the best predictor (approximately 33%) of the observed interpopulation variation in estimates of CHD mortality rate (Pr=0.10). Variation in the relative frequency of the epsilon4 allele predicted approximately 50% of interpopulation variation in average serum total cholesterol level (Pr=0.02) and 75% of the variation in CHD mortality rate (Pr=0.002) when information about variation in the other risk factors and the epsilon2 and epsilon3 alleles is ignored. Furthermore, variation in the relative frequency of the epsilon4 allele predicted approximately 40% of the variation in CHD mortality rate (Pr=0.02) after considering the contribution of variation in average serum total cholesterol level. Average serum total cholesterol level was estimated to increase by 0.114 mmol/l (4.405 mg/dl), and CHD mortality rate by 24.5/100000, for an increase of 0.01 in the relative frequency of the epsilon4 allele. The predictive utility of the epsilon2 and epsilon3 alleles was considerably less than that of the epsilon4 allele. For the sample of populations considered, the geographic distribution of the apoE alleles can be a statistically significant predictor of interpopulation variation in both the average serum total cholesterol level and CHD mortality rate. In particular, the epsilon4 allele may confer valuable ecological risk information.

Effects of medroxyprogesterone acetate on hepatic glucose metabolism and microsomal enzyme activity in rats with normal and altered liver.

Effects of medroxyprogesterone acetate (MPA) on hepatic glucose handling and drug metabolism were investigated in female rats with intact and damaged liver. Hepatic glucose-6-phosphatase activity, glycogen content and fasting blood glucose were assessed as indices of glucose metabolism. Cytochrome P-450 content and NADPH-cytochrome P-450 reductase activity were assayed to reflect liver drug metabolism. Liver injury was induced by dimethylnitrosamine and carbon tetrachloride. The results demonstrate that hepatic glucose handling and drug metabolism were changed in a parallel fashion in intact, damaged and induced liver. The MPA-induced changes in glucose metabolism were slight in intact animals, whereas the compound has an increasing effect on glucose and drug metabolism in rats with damaged liver. The findings demonstrate the MPA enhances the normallization of hepatic glucose and drug metabolism in damaged liver.