Current Drug Metabolism, Volume 4, Number 1, 2003
Retinoic Acid Metabolism and Mechanism of
Action: A Review Pp. 1-10
Julie Marill, Nadia Idres, Claude C. Capron,
Eric Nguyen, and Guy G. Chabot
DNA Demethylating Agents and
Chromatin-Remodelling Drugs: Which, How and Why? Pp. 11-31
Ana Villar-Garea and Manel Esteller
Drug Metabolism and Individualized Medicine Pp. 33-44
Pratima Srivastava
Cancer and Phase II Drug-Metabolizing Enzymes Pp. 45-58
Sheweita, S.A. and Tilmisany, A.K.
A Nuclear Receptor-Mediated Xenobiotic
Response and Its Implication in Drug Metabolism and Host Protection Pp. 59-72
J. Sonoda, J.M. Rosenfeld, L. Xu, R.M. Evans,
and W. Xie
Kidney CYP450 Enzymes: Biological Actions
Beyond Drug Metabolism Pp.
73-84
X. Zhao and J.D. Imig
Abstracts
[Back to top] Retinoic Acid Metabolism and Mechanism of
Action: A Review
Julie Marill, Nadia Idres, Claude C. Capron,
Eric Nguyen, and Guy G. Chabot
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 RARa.
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.
[Back to top] DNA Demethylating Agents and Chromatin-Remodelling Drugs:
Which, How and Why?
Ana Villar-Garea and Manel Esteller
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.
[Back to top] Drug Metabolism and Individualized Medicine
Pratima Srivastava
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.
[Back to top] Cancer and Phase II Drug-Metabolizing Enzymes
Sheweita, S.A. and Tilmisany, A.K.
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, GSTpserves 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.
[Back to top] A Nuclear Receptor-Mediated Xenobiotic
Response and Its Implication in Drug Metabolism and Host Protection
J. Sonoda, J.M. Rosenfeld, L. Xu, R.M. Evans,
and W. Xie
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.
[Back to top] Kidney CYP450 Enzymes: Biological Actions
Beyond Drug Metabolism
X. Zhao and J.D. Imig
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.