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Biomedical subjects

A Rautio

Publications and source records attributed to A Rautio.

At least 19 recordsLinked to original sources
PubMed2005

Low level of tissue plasminogen activator activity in non-diabetic patients with a first myocardial infarction.

OBJECTIVE: To explore the role of tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) in survivors of a first myocardial infarction (MI). Insulin and proinsulin were analysed as potential risk factors. DESIGN: Case-control study in northern Sweden. SUBJECTS: A total of 115 patients under 65 years of age with a first MI were enrolled and recalled for further examination 3 months later. Twenty-seven patients were excluded, 17 with known diabetes and 10 who did not come to the follow-up, giving a final number of 88 patients, 73 men and 15 women. Patients were age- and sex-matched with control subjects drawn from the local cohort in the MONICA population survey 1994. MAIN OUTCOME MEASURES: We compared MI patients and controls using univariate and multiple regression analyses including odds ratios (OR). RESULTS: PAI-1 activity, fibrinogen, postload insulin and -proinsulin were significantly higher and tPA activity significantly lower in MI patients in the univariate analysis. In a multiple regression analysis, including also age, sex and cardiovascular risk factors, these parameters were divided in quartiles. The lowest quartile of tPA activity was significantly associated with MI (OR = 19.1; CI 3.0-123) together with the highest quartiles of fibrinogen (OR = 25; CI 5.2-120) but other variables were not. CONCLUSION: Low tPA activity, i.e. low fibrinolytic activity, characterized nondiabetic subjects after a first MI which is not explained by concomitant disturbances in metabolic and anthropometric variables.

Analysis of Variance↗
PubMed2005

Favourable trends in the incidence and outcome of myocardial infarction in nondiabetic, but not in diabetic, subjects: findings from the MONICA myocardial infarction registry in northern Sweden in 1989-2000.

BACKGROUND: The aim of this study was to compare time trends in incidence, case fatality and mortality due to myocardial infarction (MI) in patients with or without diabetes. METHODS: This study was based on the Northern Sweden MONICA Project MI registry with a target population of about 200,000 inhabitants in the age group 35--64 years in the two northernmost counties of Sweden. During 1989--2000, 6254 patients who had had an MI according to MONICA criteria were included in this study: 4569 patients had a first MI and 1685 had a recurrent MI. Sixteen per cent of the men and 20% of the women had had diabetes mellitus diagnosed prior the MI. RESULTS: Over the 12-year period, there was a declining trend in incidence and case fatality in first MI. Also, the event rates (first ever and recurrent MI) declined in men without diabetes. In women without diabetes favourable time trends were seen in first ever MI, recurrent MI and in case fatality. There were no favourable time trends for any of these outcomes in patients with diabetes. CONCLUSION: In nondiabetic subjects below the age of 65, the incidence of, and case-fatality in, MI declined. This led to a decreased mortality over the 12-year period. These favourable trends over time were not observed in diabetic subjects.

Adult↗
PubMed2001

Polymorphisms of CYP2A6 and its practical consequences.

CYP2A6 is an hepatic enzyme predominantly with some expression in specialized extrahepatic cell types. The CYP2A6 enzyme has a somewhat restricted active site, accepting only a few xenobiotics as substrates. Interest in CYP2A6 has risen considerably after nicotine and some tobacco specific nitrosamines were established as high-affinity substrates for this enzyme. Recently, the organization and structures of the CYP2A gene cluster and several polymorphic alleles of the CYP2A6 gene have been characterized. Two alleles with a point mutation and at least three different types of gene deletion, all leading to deficient gene function, have been found. The frequencies of these alleles vary considerably among different ethnic populations, the deletion alleles being most common in Orientals (up to 20%). The frequency of point mutations are low in all populations studied thus far (< 3%). Several case-control studies have addressed the relationship between CYP2A6 status and smoking habits as well as the role of CYP2A6 polymorphism in lung cancer risk. Studies in Japanese suggest that CYP2A6 poor metabolizer genotypes result in altered nicotine kinetics and may lower cigarette smoking elicited lung cancer risk, whereas similar studies in Caucasian populations have not revealed any clear associations between variant CYP2A6 genotypes and smoking behaviour or lung cancer predisposition.

Alleles↗
PubMed2000

CYP2A6: a human coumarin 7-hydroxylase.

Coumarin 7-hydroxylation is catalysed by a high-affinity CYP2A6 enzyme in human liver microsomes. CYP2A6 is the only enzyme catalysing this reaction and consequently the formation of 7-hydroxycoumarin can be used as 'an in vitro and in vivo probe' for CYP2A6. CYP2A6 is a major contributor to the oxidative metabolism of nicotine and cotinine, and it also contributes, to a larger or smaller extent, to the metabolism of a few pharmaceuticals (e.g. fadrozole), nitrosamines, other carcinogens (e.g. aflatoxin B1) and a number of coumarin-type alkaloids. CYP2A6 may be inducible by antiepileptic drugs and it is decreased in alcohol-induced severe liver cirrhosis. Several mutated or deleted CYP2A6 alleles have been characterized. Although CYP2A6 represent up to 15% of human microsomes P450 proteins, it is still one of the less well characterised cytochrome P450 enzymes.

Anticoagulants↗
PubMed1999

Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism.

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C-oxidase. A relationship between CYP2A6 genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re-evaluated the genotyping method used for the CYP2A6*3 allele and found that a gene conversion in the 3' flanking region of 30-40% of CYP2A6*1 alleles results in genotype misclassification. In fact, no true CYP2A6*3 alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6 gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6 alleles as a consequence of CYP2A6/CYP2A7 gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6 alleles.

Apoproteins↗
PubMed1999

N-acetyltransferase-2 polymorphism, smoking and type 1 diabetic nephropathy.

The N-acetyltransferase (NAT2) polymorphism has been suggested to be related to diabetic microvascular complications. To study the distribution of NAT2 genotypes in Caucasian type 1 diabetic patients with and without diabetic nephropathy, 214 adult type 1 diabetic patients and 53 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism. In addition, 75 young type 1 diabetic patients were genotyped, and 70 of them also phenotyped by caffeine. Of the adult patients, 83 had normal albumin excretion, 58 had microalbuminuria, and 73 had overt diabetic nephropathy. NAT2 allele frequencies were similarly distributed between the diabetic patients and healthy individuals: 0.29/0.2 5 (NAT2*4), 0.03/0.04 (NAT2*7B), 0.25/0.27 (NAT2*6A), and 0.43/0.44 (NAT2*5B), and within the diabetic subgroups. Because smoking is a known risk factor for diabetic nephropathy, nonsmoking and smoking patients were analysed separately. NAT2 allele frequencies differed significantly between the nonsmoking normoalbuminuric, microalbuminuric and nephropathic patients: 0.18/0.41/0.30 (NAT2*4), 0.04/0.00/0.02 (NAT2*7B), 0.35/0.18/0.17 (NAT2*6A), 0.43/0.41/0.50 (NAT2*5B), P = 0.013. In nonsmoking fast acetylators odds ratio for microalbuminuria and nephropathy was 3.1 (95% confidence interval 1.36-7.05), P = 0.007 by logistic regression. In smokers, a nonsignificant odds ratio was found [0.31 (95% confidence interval 0.08-1.2), P = 0.09]. Smoking is a strong confounding factor in relation to NAT2 analyses and diabetic nephropathy. According to our data, in nonsmoking type 1 diabetic patients fast NAT2 genotype implies an increased risk for diabetic nephropathy.

Adult↗
PubMed1999

Xenobiotic-metabolizing enzymes and cancer risk: correspondence between genotype and phenotype.

Metabolic activation and/or inactivation of a carcinogen is usually studied in appropriate in vitro systems but ultimately needs confirmation from in vivo studies, i.e. phenotype studies. It determines what initially happens to a carcinogen to which an organism is exposed. Consequently, it is of major importance to investigate the correspondence between any particular genotype of a carcinogen-metabolizing enzyme and its phenotypic expression, if any. The need to elucidate the relationship between genotype and phenotype is particularly important now, when methods for uncovering changes in genomic DNA are rather easy, even routine. There are several examples where the correspondence between a variant allele and an altered phenotype, measured by a probe drug or by some other means, has been elucidated (e.g. several alleles of CYP2D6). However, there are also cases where this correspondence has either not been studied (sometimes because of a lack of suitable probe substances) or has remained unclear (e.g. CYP1A1 or CYP2E1), despite case-control studies demonstrating an association between a variant allele and cancer risk. In the end one has to address the basic question as to how the genotype determines the phenotype and whether there is any biologically plausible link between the genotypic differences and cancer susceptibility. A knowledge of the complete sequence of events, from the gene to the outcome, would be helpful in unravelling the implications and possible preventive and treatment strategies to be employed in cases where clear associations between carcinogen-metabolizing enzymes and cancer susceptibility have been uncovered.

Alleles↗
PubMed1999

The CYP2A subfamily: function, expression and genetic polymorphism.

The CYP2A6 gene is one of the three members of the human CYP2A gene subfamily, the others being CYP2A7 and CYP2A13. The CYP2A6 enzyme catalyses the oxidation of several compounds that have clinical or toxicological interest, including pharmaceuticals, procarcinogens, and tobacco smoke constituents. CYP2A6 is expressed mainly in liver, and only trace amounts are found in extrahepatic tissues. Coumarin is a high-affinity substrate for CYP2A6, and a phenotyping test based on coumarin 7-hydroxylation has been developed. Two mutant alleles of the CYP2A6 gene have been found, i.e. CYP2A6*2 and CYP2A6*3. Homozygosity for both mutated alleles appears to confer a poor metabolizer (PM) phenotype, detectable by slow or non-existent 7-hydroxylation of coumarin. Very little is known about the inducibility and regulation of CYP2A6, but studies on the mouse orthologue, CYP2A5, have revealed novel pathways for induction. Since CYP2A6 polymorphism was found fairly recently, nothing is known presently about associations between variant CYP2A6 alleles and diseases or other adverse outcomes of exposure to toxins. Such studies, however, are clearly warranted, given the wide range of procarcinogens and other toxins metabolized by the CYP2A6 enzyme.

Animals↗
PubMed1998

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.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Hepatitis A impairs the function of human hepatic CYP2A6 in vivo.

Hepatitis virus A (HVA) is a worldwide sporadic disease but its effects on pharmacokinetics and individual drug responses have not been studied. In this study, the 7-hydroxycoumarin (7OHC) excretion test used in vivo as a bioindex of hepatic CYP2A6 activity was performed in 20, previously healthy, acute jaundice HVA patients. Volunteers with an acute HVA were treated with one p.o. administration of 5 mg coumarin (Venalot). Among the patients, 11 were children (6-10 years; two girls and nine boys), the rest (15-40 years old) consisted of two men and seven women. Urinary excretion of 7OHC was measured after overnight fasting in four fractions: 0 h before any medication (to detect if any basal 7OHC excretion exits), and after a 5-mg coumarin capsule p.o., 0-2, 2-4 and 4-8 h fractions were collected and urine volumes were recorded. Urinary excretion of 7-hydroxycoumarin occurred to a similar extent in healthy adults and children. The first 2-h 7OHC excretion was decreased by 26% (P < 0.05) and total (0-8 h) 7OHC excretion was decreased by 37% (P<0.01) among HVA-positive adults (age range 15-40 years) compared with the values obtained from healthy volunteers. In 11 HVA-positive children (age 6-10 years), the first 2-h 7OHC excretion was only 20% (P < 0.0001) and the total 7OHC excretion 28% (P < 0.0001) of the value observed in healthy controls. These results suggest that (i) an acute HVA decreases the metabolic clearance of drugs such as coumarin which are rapidly metabolised by CYP2A6 and (ii) this decrease is even more prominent in children. Such metabolic responses may be of clinical importance and may also interfere with other drug therapy in these patients.

Adolescent↗
PubMed1996

Coumarin 7-hydroxylation in long-term adherents of a strict uncooked vegan diet.

OBJECTIVE: Coumarin 7-hydroxylation was investigated in 21 Finnish vegans (20 females, one male) consuming a strict, uncooked vegan diet ("living food diet") and in their matched omnivorous controls, by means of an in vivo coumarin test. METHOD: A capsule containing 5 mg of coumarin (Venalot) was taken after an overnight fast, and urine samples were collected before and 2, 4 and 6 h after the drug administration. The extent and rate of urinary excretion of 7-hydroxycoumarin was determined using HPLC. RESULTS: The total urinary excretion of 7-hydroxycoumarin during 6 h was 58 (range 23-85) and 64 (range 39-92)% of the administred dose in the vegan and control groups. The coumarin index (excretion of 7-hydroxycoumarin during the first 2 h as percentage of total excretion) was 72% in the vegan and 78% in the control groups. A negative correlation was observed between the coumarin index and the consumption of wheatgrass juice by the vegans (r = -0.60, P < 0.01, n = 21). Proportion of slow hydroxylators (excreting 7-hydroxycoumarin after 4 h) was not statistically different between the groups (5/21 in the vegans vs 8/20 in the controls). CONCLUSION: According to the present study, the clearly different dietary patterns and nutrient intakes between the vegans and the omnivores resulted in similar extent and rate of 7-hydroxycoumarin formation, indicating only a minor effect on coumarin hydroxylase (CYP2A6) activity by the plant substances in the uncooked vegan diet.

Adult↗
PubMed1995

Serum sex hormone levels after replacing carbamazepine with oxcarbazepine.

The function of the hepatic P450 enzyme system was evaluated by measuring the kinetics of antipyrine and serum sex hormone levels were determined in 12 male patients with epilepsy during carbamazepine medication, and two and six months after changing their medication to oxcarbazepine. Antipyrine t1/2 increased and antipyrine CL decreased after the change reflecting normalisation of the liver P450 enzyme system function. Serum sex hormone binding globulin levels decreased, and serum dehydroepiandrosterone sulphate increased after the change. The results show that the carbamazepine-associated induction of the liver P450 enzyme system and changes in serum sex hormone balance can be avoided by replacing carbamazepine with oxcarbazepine.

Adult↗
PubMed1995

Antipyrine, coumarin and glipizide affect n-acetylation measured by caffeine test.

The effect of various treatments on acetylation status measured by caffeine metabolites was investigated in 17 subjects with non-insulin dependent diabetes mellitus (NIDDM). The test drugs, caffeine (200 mg), antipyrine (20 mg/kg) and coumarin (5 mg), were given simultaneously, and urinary 5-acetylamino-6-formyl-amino-3-methyluracil/1-methylxanthine (AFMU/1X) molar ratio was measured before and after 8 weeks of therapy. The urinary AFMU/1X molar ratio decreased (p < 0.05) after 8 weeks of therapy with glipizide (2.5 mg), but remained unaltered in those treated with placebo or those who self-monitored blood glucose (SMBG) by glucometer. Antipyrine and coumarin decreased (p < 0.05) the AFMU/1X molar ratio both in diabetics and healthy volunteers. Our data demonstrate that glipizide, antipyrine and coumarin may interfere with the classification of acetylator status measured by caffeine metabolites.

Acetylation↗
PubMed1995

CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.

1. The in vitro hepatic metabolism of lignocaine to monoethylglycinexylide (MEGX) is mediated by CYP3A4 and that of coumarin to 7-hydroxycoumarin (7OHC) by CYP2A6. We investigated the usefulness of monitoring serum MEGX concentrations (after 1 mg kg-1 lignocaine i.v.) and urinary 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12) disease and in control subjects (n = 20). The extent of liver disease was assessed using measurements of serum aminoterminal propeptide (PIIINP) and Child-Pugh grades. 2. Serum concentrations of MEGX were decreased in severe (4.6 +/- 3.0 s.d. ng ml-1), moderate (19.1 +/- 11.6 s.d. ng ml-1) and mild (32.8 +/- 14.2 s.d ng ml-1) liver disease as compared with controls (53.4 +/- 15.8 s.d ng ml-1). The excretion of 7OHC over 2 h was decreased in severe (18.0 +/- 10.3 s.d % of dose) and moderate (34.2 +/- 15.6 s.d %), but not in mild (49.7 +/- 19.0 s.d %) liver disease as compared with that in controls (56.2 +/- 11.6%). 3. In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/- 13.2 s.d %) suggesting enzyme induction. In contrast, serum MEGX concentration were low (40.0 +/- 14.1 s.d ng ml-1), possibly due to competition for CYP3A4 between lignocaine and antiepileptic drugs. 4. In patients with kidney disease serum MEGX concentration (56.5 +/- 26.1 s.d ng ml-1) was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Thyroid and myocardial function after replacement of carbamazepine by oxcarbazepine.

We determined changes in serum concentrations of thyroid hormones during carbamazepine (CBZ) therapy during a 5-year prospective follow-up study of 20 patients with newly diagnosed epilepsy. In addition, we evaluated the effects of replacing CBZ with oxcarbazepine (OCBZ) in 12 male patients with epilepsy in a 6-month prospective follow-up study. Circulating thyroxine and free thyroxine levels decreased after 2-month CBZ treatment and remained at a low level during the 5-year follow-up. There were no associated changes in serum thyrotropin (TSH) concentrations. When CBZ was replaced by OCBZ, the function of the liver's P450 enzyme system normalized, as shown by an increase in antipyrineT1/2, and a decrease in antipyrineCL. Serum total and free thyroxine levels increased, and thereafter serum TSH levels decreased. Indexes of diastolic heart function improved concomitantly, which may reflect subclinical hypothyroidism at the cellular level during CBZ treatment. We conclude that normal thyroid function can be restored in patients with epilepsy by replacing CBZ with OCBZ.

Adolescent↗