Current Drug Metabolism - Volume 4, Issue 1, 2003

Retinoids are vitamin A (retinol) derivatives essential for normal embryo development and epithelial differentiation. These compounds are also involved in chemoprevention and differentiation therapy of some cancers, with particularly impressive results in the management of acute promyelocytic leukemia (APL). Although highly effective in APL therapy, resistance to retinoic acid (RA) develops rapidly. The causes of this resistance are not completely understood and the following factors have been involved: increased metabolism, increased expression of RA binding proteins, P-glycoprotein expression, and mutations in the ligand binding domain of RARα. RA exerts its molecular actions mainly through RAR and RXR nuclear receptors. In addition to the nuclear receptor based mechanism of RA action, covalent binding of RA to cell macromolecules has been reported. RA derives from retinol by oxidation through retinol and retinal dehydrogenases, and several cytochrome P450s (CYPs). RA is thereafter oxidized to several metabolites by a panel of CYPs that differs for the different RA isomers. Phase II metabolism, mainly glucuronidation, is also observed. The role RA metabolism plays in the expression of its biological actions is not completely understood: in several systems, metabolism decreases RA activity, whereas in other systems metabolism appears involved in its action. In addition, several RA metabolites have shown activity and cannot be classified as only catabolites. Therapy of cancer with retinoids is still in its infancy, but the use of new analogues with improved pharmacological properties, along with combination with other drugs, could undoubtedly improve the management of several cancers in the future.

DNA hypermethylation at the CpG dinucleotides clustered in “islands” in the promoter regions of genes causes transcriptional repression through the remodelling of chromatin. Aberrant methylation patterns of tumor suppressor genes and their subsequent silencing constitute a common feature of many cancers. Thus, the search for drugs that interfere in methylation-mediated gene repression has become one of the major goals in the design of cancer therapies. The major actors in the mammalian methylation system are DNA-methyltransferases (DNMTs), and methyl-CpG-binding proteins (MBDs), which recognize methylated cytosine and recruit repressor complexes, including histone deacetylases (HDACs). In this context, two major groups of drugs can be distinguished. The first one is constituted by substances that inhibit the action of DNMTs, either competing with cytosine or with S-adenosylmethionine (SAM, AdoMet) or acting over the DNMTs themselves. The second group involves compounds that inhibit subunits of the repressor complexes, such as HDACs. In this manuscript we review these two different groups of drugs, discussing their properties and the side-efects that have been described (that occur by interference with other metabolic pathways). We also propose the logical pharmacological extension of these findings to design more specific and efective drugs for the prevention and treatment of human cancer.

Drug metabolism refers to the biochemical transformation of a compound into another more polar chemical form. Absorption, distribution, metabolism and excretion comprise an integral part in understanding the safety and efficacy of a potential new drug. Detailed in-depth knowledge of the Pharmacokinetics and Drug Metabolism of a new drug entity is considered a prerequisite to know the appropriate route of administration, correct dose etc. Sometimes there is (are) different / unwanted effect(s) of certain drugs in different populations. This is particularly true for the drug having narrow therapeutic index. Often these different effects are detrimental to an individual, thus termed as adverse drug reactions. After the raw draft of human genome has evolved, it has become increasingly clear that change(s) in the drug response between individuals, is due to the occurrence of genetic polymorphisms in the Phase I and II drug metabolizing enzymes, due to which distinct subgroups in the population differ in their ability to perform certain drug biotransformation reactions. The study about the occurrence of genetic polymorphisms in drug metabolizing enzymes is termed as Pharmacogenetics / Pharmacogenomics. Pharmacogenetic characterization of particular drug can be both phenotypically or genotypically conducted in population groups. The study is very important to check the post-marketed drug withdrawal, if a particular percentage of population suffers from adverse drug reactions, and thus a lot of revenue be saved. The study also helps to find out Right Medicine for Right Individual or Individualized Medicine.

Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GSTπ serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O6-alkylguanine in DNA leads to very high rates of G:C®A:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by overriding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.

Regulation of the Phase I CYP enzymes and Phase II conjugating enzymes is implicated in both drug metabolism and drug-drug interactions. Moreover, the elimination of numerous xenobiotic and endobiotic toxic chemicals also requires a concerted function of Phase I and II enzymes, as well as the membrane spanning drug transporters. The genes that encode these enzymes and transporters are inducible by numerous xenobiotics, yet the inducibility shows clear species specificity. In the last 3-4 years, orphan nuclear receptors (NRs) such as PXR, CAR, and FXR have been established as species-specific xeno-sensors that regulate the expression of Phase I and II enzymes, as well as selected drug transporters. This transcriptional regulation is achieved by binding of these xenobiotic receptors to the NR response elements found within the promoter regions of target genes. The identification of NRs as xenosensors represents a major step forward in understanding the genetic mechanisms controlling the expression of drug metabolizing enzymes. The establishment of NR-mediated and mechanism-guided xenobiotic screening systems by using cultured cells or genetically engineered mouse models has not only advanced our understanding of the molecular complexity of this drug-induced xenobiotic response, but has also provided in vitro and in vivo platforms to facilitate the development of safer drugs.

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), their corresponding dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). These arachidonic acid metabolites are involved in the regulation of renal epithelial transport and vascular function. 20- HETE and EETs are produced in the renal microvascular smooth muscle cells and endothelial cells, respectively. 20-HETE constricts the preglomerular arterioles by inhibiting K+ channels, and contributes importantly to renal blood flow autoregulatory responsiveness of the afferent arterioles. EETs dilate the preglomerular arterioles by activating the renal smooth muscle cell Ca2+-activated K+ channels and hyperpolarizing smooth muscle cells. These EET actions are consistent with their identification as endotheliumderived hyperpolarizing factors (EDHFs). In the kidney, EETs and 20-HETE are also produced in the proximal tubule and the thick ascending loop of Henle, and these metabolites modulate ion transport in the proximal tubules and the thick ascending limb by inhibiting Na+-K+-ATPase and the Na+-K+-2Cl- cotransporter. CYP450 metabolites also act as second messengers for many paracrine and hormonal agents, including endothelin, nitric oxide, and angiotensin II. The production of kidney CYP450 arachidonic acid metabolites is altered in diabetes, pregnancy, hepatorenal syndrome, and in various models of hypertension, and it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.