Janne Hukkanen

Janne Hukkanen
University of Oulu · Department of Internal Medicine

MD, PhD, Professor of Internal Medicine

About

60
Publications
26,232
Reads
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5,377
Citations
Additional affiliations
January 2019 - present
University of Oulu
Position
  • Professor
November 2008 - present
Oulu University Hospital
Position
  • Internist
January 2006 - October 2008
Oulu University Hospital
Position
  • Medical Doctor

Publications

Publications (60)
Article
Background Mechanisms mediating hypertensive effects of overweight and obesity have not been fully elucidated. We showed previously that activation of pregnane X receptor (PXR) by rifampicin elevates 24‐hour blood pressure (BP) and plasma 4β‐hydroxycholesterol (4βHC), agonist for liver X receptor (LXR). Methods and Results In combined “PXR activat...
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Full-text available
Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narro...
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Background & Aims Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic...
Article
Background/aim: Prompted by the increasing demand of non-invasive diagnostic tools for screening of gastric cancer (GC) risk conditions, i.e., atrophic gastritis (AG) and Helicobacter pylori (Hp) infection, the GastroPanel® test (GP: biomarker panel of PGI, PGII, G-17, Hp IgG ELISA) that was developed in the early 2000's, was recently updated to a...
Article
Full-text available
Pregnane X receptor (PXR) is a xenobiotic‐sensing nuclear receptor that regulates drug metabolism in the liver and intestine. In our clinical trials on healthy volunteers to discover novel metabolic functions of PXR activation, we observed that rifampicin, a well‐established ligand for human PXR, 600 mg daily for a week, increased the plasma alkali...
Article
Background and purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. The mechanisms involved are poorly defined precluding efficient prediction and prevention. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regu...
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Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesiz...
Article
On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly appro...
Article
Background Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces risk of premature mortality. However, some reports have suggested that RYGB may predispose to adverse health outcomes such as increased risk of inflammatory bowel disease (IBD) and colorectal cancer. Objectives...
Article
We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, cross‐over, single‐blind and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24hr ambulatory BP was monitored at the end of...
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Full-text available
Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers...
Article
Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and M...
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A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with...
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We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer’s disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer’s disease. Introduction To in...
Article
Scope To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with the metabolic syndrome. Methods and Results Subjects with the metabolic syndrome underwent an 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average ha...
Article
Cholesterol oxidation product 4β‑hydroxycholesterol (4β‑OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4β‑OHC plasma or serum levels, may be of clinical significance. The plasma and serum...
Article
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes an enormous burden to human health and health-care systems all over the world. A great proportion of this burden results from increased risk of cardiovascular diseases. Atrial fibrillation (AF) is the most common chronic heart arrhythmia globally and it increases the risk of e...
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Pregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance...
Article
The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR was originally identified to regulate drug-metabolizing enzymes and transporters. During the last ten years it has become clear that PXR harbors broader functions. Evidence obtaine...
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Background: Diet has a great impact on the risk of developing features of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVD). We evaluated whether a long-term healthy Nordic diet (ND) can modify the expression of inflammation and lipid metabolism-related genes in peripheral blood mononuclear cells (PBMCs)...
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Full-text available
Background: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known. Objective: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome. Methods: Men and women (n = 200) with features of...
Article
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We recently showed that pregnane X receptor (PXR) agonists cause hyperglycaemia during oral glucose tolerance test (OGTT) in rats and healthy volunteers (Rifa-1 study). We now aimed to determine if the secretion of incretin hormones, especially glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are affected by PXR agonists si...
Article
Atorvastatin is known to both inhibit and induce cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer-term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as mea...
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Full-text available
Previously, a healthy Nordic diet (ND) has been shown to have beneficial health effects close to those of Mediterranean diets. The objective was to explore whether the ND has an impact on gene expression in abdominal subcutaneous adipose tissue (SAT) and whether changes in gene expression are associated with clinical and biochemical effects. Obese...
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Background and aim: Few studies have explored the possible plasma cholesterol lowering effects of rye consumption. The aim of this secondary analysis in the SYSDIET study was to investigate the association between plasma alkylresorcinols (AR), a biomarker for whole grain wheat and rye intake, and blood lipid concentrations in a population with met...
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Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on card...
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The Nordic countries collaborate in setting recommendations for intake of nutrients by publishing the Nordic Nutrition Recommendations (NNR). Studies exploring how well the Nordic population adheres to the NNR are limited and none are available for the metabolic syndrome (MetS) subgroup. Individuals with MetS are a large part of the adult Nordic po...
Article
Abstract Pregnane X receptor (PXR), a ligand-activated nuclear receptor, was originally identified as a regulator of drug and bile acid metabolism. Studies in experimental animals and humans within the last decade have revealed PXR as a regulator of energy metabolism repressing gluconeogenesis and hepatic lipid oxidation. The most recent in vivo st...
Article
We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of pregnane X receptor (PXR) agonist rifampin on oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for seven days and OGTT was performed on the eighth day. The mean incrementa...
Article
Full-text available
Background: Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. Methods: We conducted a randomized dietary study lasting for 18-24 weeks in individuals wit...
Article
The induction of drug-metabolizing enzymes is a special case of pharmacokinetic interactions with consequences for the concurrent drug therapy. The most important enzymes affecting the pharmacokinetics of pharmaceuticals are cytochrome P450 (CYP) enzymes and their induction is often of utmost importance for the effects of the metabolized drugs. Thi...
Article
Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. The study had a single-blind, randomized, crossover two-arm design. Twel...
Article
Both liquorice and thiazide diuretics have hypokalaemic effects. In spite of their prevalent use, there are no studies on hypokalaemia caused by the combination of liquorice and thiazides. We recruited 10 healthy volunteers in order to study the effects of 32 g liquorice alone or in combination with 25mg hydrochlorothiazide a day for 2 weeks. The t...
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Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT),...
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Full-text available
Variability of drug metabolism, especially that of the most important phase I enzymes or cytochrome P450 (CYP) enzymes, is an important complicating factor in many areas of pharmacology and toxicology, in drug development, preclinical toxicity studies, clinical trials, drug therapy, environmental exposures and risk assessment. These frequently enor...
Article
Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme and transporters such as P-glycoprotein and organic anion transporting polypeptides, leading to clinically important interactions. Our objective was to study the effect of grapefruit juice on the pharmacokinetics of nicotine, which is primarily metabolized by the CYP2A6 enzyme...
Article
The phase of the menstrual cycle has been reported to affect frequency of smoking, withdrawal symptoms, and the likelihood of smoking cessation in women. Cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Our objective was to evaluate the effect of the phase of the menstrual cycle on the activity of CYP2A6 and the ca...
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Full-text available
Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkalo...
Article
Background/AimsGrapefruit juice is a strong inhibitor of CYP3A4 leading to clinically important interactions. The aim was to study the effect of grapefruit juice on the metabolism of nicotine, primarily a CYP2A6 substrate.Methods10 volunteers were given 2 mg oral dose of deuterium-labeled nicotine on three occasions together with 1 L of water, grap...
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Full-text available
CYP3A5 is the major CYP3A form in the human lung, and it is inducible by dexamethasone in the human A549 lung adenocarcinoma cell line. In the present study, we characterized the nature and mechanism of this induction process. The induction of CYP3A5 mRNA was assessed by quantitative reverse transcriptase-polymerase chain reaction in A549 cells. Ab...
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Pathogenesis of lung diseases, such as lung cancer and chronic obstructive pulmonary disease, is tightly linked to exposure to environmental chemicals, most notably tobacco smoke. Many of the compounds associated with these diseases require an enzymatic activation to exert their deleterious effects on pulmonary cells. These activation reactions are...
Article
Induction is defined as the increase in the amount and activity of a drug-metabolising enzyme, which is a long-term (hours and days) consequence of a chemical exposure. Previously, the study of induction of drug metabolism was largely empirical and phenomenological, and prediction beyond the compounds under actual study was practically impossible....
Article
The lung is a major target for all inhaled toxicants. Many inhaled chemicals are not hazardous as such, but are biotransformed to reactive intermediates. Therefore, the pathogenesis of interstitial and other lung diseases is intimately linked to exposure to environmental and other chemicals, which may be causative or modifying factors in the cellul...
Article
Variability in the expression of enzymes metabolizing carcinogens derived from cigarette smoke may contribute to individual susceptibility to pulmonary carcinogenesis. This study was designed to determine the effects of smoking and 3 major cytochrome P450 (CYP) enzymes, i.e., CYP1A1, CYP1B1 and CYP3A, which metabolize polycyclic aromatic hydrocarbo...
Article
Full-text available
Several cytochrome P450 (CYP) enzymes are expressed in the human lung, where they participate in metabolic inactivation and activation of numerous exogenous and endogenous compounds. In this study, the expression pattern of all known xenobiotic-metabolizing CYP genes was characterized in the human alveolar type II cell-derived A549 adenocarcinoma c...
Article
The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have reve...
Article
Members of the human cytochrome P450 2A (CYP2A) subfamily are known to metabolize several promutagens, procarcinogens, and pharmaceuticals. In this study, the expression of the three genes found in the human CYP2A gene cluster was investigated in the liver and several extrahepatic tissues by gene-specific reverse transcriptase-polymerase chain reac...
Article
Long-term tamoxifen therapy is associated with increased risk of uterine endometrial cancer and benign alterations. Tamoxifen is metabolized to reactive intermediates by endometrial tissue, and tamoxifen therapy-induced DNA adducts have been found in human endometrium. Since metabolic activation is often catalyzed by cytochrome P450 (CYP) enzymes,...
Article
The purpose of the study was to obtain a comprehensive picture of the expression of cytochrome P450s (CYP) in the human lung, broncho-alveolar macrophages (BAM), and peripheral blood lymphocytes. The methods used were reverse transcriptase-polymerase chain reaction (RT-PCR) with gene-specific primers and immunohistochemistry with specific anti-pept...
Article
Human pulmonary tissue are known to contain enzymes mediating procarcinogen activation. Peripheral blood lymphocytes and bronchoalveolar macrophages (BAMs) have been used as surrogates for the lung in studies involving cytochrome P450 (CYP) parameters, including CYP1A1 inducibility in relation to susceptibility to lung cancer. In this study, a comp...
Article
Expression in the lung of procarcinogen-metabolizing P450 enzymes in the CYP3A subfamily may contribute to the initiation of pulmonary carcinogenesis by agents that require metabolic activation, such as tobacco-derived polycyclic aromatic hydrocarbons. Expression and localization of CYP3A4 and CYP3A5 proteins in human lung were determined by immuno...
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Full-text available
Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. T...
Article
The expression of individual xenobiotic-metabolizing cytochrome P450 (CYP) genes in human placenta was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). mRNAs of CYP1A1, CYP2E1, CYP2F1, CYP3A3/4, CYP3A5, and CYP4B1 were detected by RT-PCR, and CYP1A2, CYP2A6/7, CYP2B6/7, CYP2C8-19, CYP2D6, and CYP3A7 were not de...

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