Research group - Anders Rane
Pharmacogenomics of drugs and steroid hormones. Our aims are to study the genetic variation in drug metabolism in relation to outcome of disease treatment, adverse drug reactions and drug interactions.
The outcome of drug treatment, or of abuse of substances such as anabolic androgenic steroids (AAS) in doping, is the result of organism-drug interactions, both at the receptor and drug disposition level. More than half of the variation in outcome is ascribed to genetic polymorphisms in drug metabolising enzymes and drug targets. The cytochrome P450 (CYP) and glucuronosyl transferase (UGTs) enzymes are important catalysts of most drugs and abused agents and are major determinants of outcome as oxidation/conjugation leads to termination of action, or bioactivation, ie formation of active or even toxic metabolites. Thus, the CYP2C9 enzyme catalyses the metabolism of drugs such as HMG CoA inhibitors (statins), anticoagulants, NSAIDs, angiotensin II receptor antagonists, antiepileptics, etc as well as the formation of vasoregulating epoxyeicosatrienoic acids (EET). As a corollary, CYP enzymes may serve as a multi-crossroad with potential significance for drug-drug and drug-endobiotic/steroid interactions with ensuing effects on the disease and its treatment. This metabolic interface is also a potential basis for clinically relevant interactions. NSAIDs have marked inhibitory effects on the COX-enzymes, but the implications of their polymorphic metabolism for prostaglandin maintenance of the vascular bed is not explored. Our experiments in endothelial HUVEC cells and isolated human vessels demonstrate an impact of NSAIDs on the vascular tone by modification of expression of antioxidative stress genes and prostacyclin. These effects seem to be compound specific.
We are also studying the intra- and interethnic genetic variation in the uptake, metabolism, and excretion of androgens (e.g such used in doping) as well as their effect on the androgen receptor
Genetic variation in the androgen metabolic network may modulate the effect and risk of adverse reactions, (eg endocrine disorders) and drug-steroid interactions. We have found extremely large genetic variation in the key enzymes involved in the network (CYPs, aldoketoreductases, phosphodiesterases, and particularly UGTs) both within, and between Caucasian and Asian groups.
To study the function of allelic variants of enzymes in metabolism of drugs and androgens in relation to disease treatment, adverse reactions, and interactions. We focus on the metabolism and drug-drug and drug-steroid interactions of statins, NSAIDs and androgenic steroids, including effect on formation of EETs. To study the variation within and between ethnic groups in pharmacogenetics of androgens in relation to their disposition, uptake and effect on the androgen receptor (AR) in an AR assay.
Consideration and more knowledge about pharmacogenetic variation in drug therapy will improve dose tailoring and optimize dosing with best possible effect and least side effects. More knowledge about reactions to, and kinetics of abused androgens and their derivatives (endogenous or exogenous) in doping is important and may improve diagnostics and treatment of such disorders.
Research group leader Anders Rane
- Clinical studies in patients and healthy volunteers.
- In vitro studies of metabolism in human subcellular fractions of liver etc, and human cell lines.
- HUVEC and other cell Iines and genotype panels of human tissue samples (liver, etc)
- Genetic variation in metabolism in patients and healthy volunteers in different ethnic groups. Steroid plasma concentrations and excretion profiles will be related to polymorphisms in androgen metabolising enzyme genes and AR response.
European Commission (TINN and NeoOpioid projects), Swedish Science Foundation, World Anti-Doping Agency, Centrum för Idrottsforskning (Swedish Center for Sports Research), Cancer Society of Stockholm, Karolinska Institutet Foundations, Some other minor sources
Testosterone challenge and androgen receptor activity in relation to UGT2B17 genotypes.
Ekström L, Cevenini L, Michelini E, Schulze J, Thörngren JO, Belanger A, et al
Eur. J. Clin. Invest. 2013 Mar;43(3):248-55
A supraphysiological dose of testosterone induces nitric oxide production and oxidative stress.
Skogastierna C, Hotzen M, Rane A, Ekström L
Eur J Prev Cardiol 2014 Aug;21(8):1049-54
Androgen sulfation in healthy UDP-glucuronosyl transferase 2B17 enzyme-deficient men.
Schulze JJ, Thörngren JO, Garle M, Ekström L, Rane A
J. Clin. Endocrinol. Metab. 2011 Nov;96(11):3440-7
Long term perturbation of endocrine parameters and cholesterol metabolism after discontinued abuse of anabolic androgenic steroids.
Gårevik N, Strahm E, Garle M, Lundmark J, Ståhle L, Ekström L, et al
J. Steroid Biochem. Mol. Biol. 2011 Nov;127(3-5):295-300
Bioavailability of testosterone enanthate dependent on genetic variation in the phosphodiesterase 7B but not on the uridine 5'-diphospho-glucuronosyltransferase (UGT2B17) gene.
Ekström L, Schulze JJ, Guillemette C, Belanger A, Rane A
Pharmacogenet. Genomics 2011 Jun;21(6):325-32