Current Pharmacogenomics - Volume 1, Issue 2, 2003

The metabolism and elimination of drugs is mainly mediated by various cytochrome P450 (CYP) enzymes, conjugative enzymes, transporters, and efflux proteins. Members of these gene families are up-regulated at transcriptional level by drug exposure, thus leading to induction of drug metabolism and elimination. There is compelling evidence that this induction is controlled by two drug-activated nuclear receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR). This mini-review summarizes the current knowledge of CAR and PXR, their DNA and ligand binding preferences, expression patterns and polymorphisms, mechanisms of activation, and target genes.

Patients vary widely in their responses to drug therapy, often manifested as adverse drug reactions, drug resistance or drug-associated toxicity. Functional polymorphisms in genes encoding enzymes, which are involved in drug action, may underlie these differences thus offering a powerful tool in predicting a treatment outcome.Several studies have addressed the potential for tailoring individual acute lymphoblastic leukemia (ALL) therapy based on patients' genetics. Several candidate genes have been shown to have a predictive role, among which the best examples are the well-characterized polymorphisms in the thiopurine methyltransferase (TPMT) gene. The impact of TPMT genotypes on 6-MP tolerance, affecting the duration of treatment and the appearance of severe hematotoxicity or secondary malignancies has been well documented. Recent studies suggest that polymorphisms in enzymes of the folate cycle may modify the therapeutic effectiveness and toxicity of antifolates. Polymorphism in the enhancer element located in 5'-UTR of thymidylate synthase gene influenced the outcome of ALL, whereas variants of methylene tetrahydrofolate reductase gene correlated with methotrexate sensitivity. Efforts have been also made to gain a closer insight into the role of polymorphisms in genes that might affect both disease susceptibility and drug metabolism, and some of them (e.g. glutathione S-transferase or quinone oxidoreductase) seem to affect the risk of recurrent disease in children with ALL.Extending the pharmacogenetics concept to other candidate genes / enzymes and to other drugs might, through comprehensive genetic evaluation, help clinical management of ALL patients.

Anti-tuberculosis drug induced (ATD) hepatotoxicity is uncommon and unpredictable. It might be related to drug itself or reactive metabolites derived from the drugs in vivo. Several demographic characteristics, such as race, age, sex, body mass index, alcohol intake, have been reported to be susceptibility risk factors for hepatotoxicity related to ATDs. There is now evidence that genetic variations or polymorphisms in biotransformation or detoxification systems controlled by NAT2, GSTM1 etc., might modulate the toxic effects of some drugs. Since prevalences of polymorphisms are different in different ethnic populations, the incidences of ATD hepatotoxicity vary in populations. Thus, knowledge of prevalences of polymorphisms in these genes in a population, prior to medication, may be useful in evaluating the risk and controlling ATD hepatotoxicity.

The identification of genetic disease susceptibility genes has been pursued with the expectation to rapidly translate causal disease mechanisms into innovative therapeutics. Indeed, several susceptibility genes have led to the elucidation of molecular pathologies and the development of new drugs and diagnostics for disease management. We review in this article how the identification of susceptibility genes for high density lipoprotein (HDL) particle deficiencies have changed our understanding of lipid metabolism and how this understanding is being used in translational research for the discovery of new treatment strategies.The identification of ATP-binding cassette transporter A1 (ABCA1) and transcriptional repressor zinc finger protein 202 (ZNF202) as susceptibility genes for coronary heart disease (CHD) and hypoalphalipoproteinemia, led to the characterization of a functional network of genes involved in lipid metabolism.Currently available drug classes for metabolic and dyslipidemic indications such as the glitazones, fibrates and statins have been shown to modulate the expression of some components involved in reverse cholesterol transport. The characterization of new regulators of this gene network that are amenable to pharmaceutical modulation such as the nuclear receptors FXR, LXR, PXR, PPAR and RXR may offer new perspectives in disease treatment, if undesirable side effects can be diminished. In addition, the characterization of ABCA1-mediated lipid efflux systems has provided new biomarkers to assess the pharmacological effects of new therapeutic strategies on reverse cholesterol transport.

Pheochromocytoma contains and may synthesize a large number of peptides such as opioids (Leu-, Met-enkephalin), VIP, gastrin, calcitonin gene related peptide (CGRP), somatostatin, and adrenocorticotrophic hormone (ACTH). Also, circulating level of these peptides may be elevated.Although the precise contribution of these peptides secretion to the clinical features are largely unknown, it can be suggested that specific endocrine system could be involved in ectopic hormone production by pheochromocytoma. Indeed, it has occasionally been reported that pheochromocytoma is associated with Cushing's syndrome resulting from excess ACTH production.As there are already many excellent reviews of this area, the discussion that follows will mainly focus on our data, including 1.Opioids, 2.Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), 3.Natriuretic peptides (NPs), 4.Leptin, 5.Endothelin 6. Angiotensin II receptor, 8. Chromogranin A and Catestatin.

Although various environmental factors, including diet and physical exercise, influence bone mass, a genetic contribution to this parameter has also been recognized. Genetic linkage analyses and candidate gene association studies have implicated several loci, and a variety of candidate genes in the regulation of bone mineral density and the pathogenesis of osteoporosis or osteoporotic fracture. However, the genes responsible for these latter conditions have not been identified definitively. I here summarize both the candidate loci identified by linkage analyses and the candidate genes examined by association studies. I also review in more detail studies that have examined the association with bone mass or with the susceptibility to osteoporosis or osteoporotic fracture of polymorphisms in the genes for the vitamin D receptor, collagen type Iα1, estrogen receptor α, interleukin-6, osteocalcin, osteoprotegerin, CC chemokine receptor 2, matrix metalloproteinase-1, and transforming growth factor-α1. Such studies may provide insight into the function of these genes as well as into the role of genetic factors in the development of osteoporosis.