Trends in Pharmacological Sciences
Current awarnessMetabolic polymorphisms affecting activation of toxic and mutagenic arylamines
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Cited by (30)
Glucuronidation in therapeutic drug monitoring
2005, Clinica Chimica ActaGlucuronidation is a major drug-metabolizing reaction in humans. A pharmacological effect of glucuronide metabolites is frequently neglected and the value of therapeutic drug monitoring has been questioned. However, this may not always be true.
In this review the impact of glucuronidation on therapeutic drug monitoring has been evaluated on the basis of a literature search and experience from the own laboratory.
The potential role of monitoring glucuronide metabolite concentrations to optimize therapeutic outcome is addressed on the basis of selected examples of drugs which are metabolized to biologically active/reactive glucuronides. Furthermore indirect effects of glucuronide metabolites on parent drug pharmacokinetics are presented. In addition, factors that may modulate the disposition of these metabolites (e.g. genetic polymorphisms, disease processes, age, and drug–drug interactions) are briefly mentioned and their relevance for the clinical situation is critically discussed.
Glucuronide metabolites can have indirect as well as direct pharmacological or toxicological effects. Although convincing evidence to support the introduction of glucuronide monitoring into clinical practice is currently missing, measurement of glucuronide concentrations may be advantageous in specific situations. If the glucuronide metabolite has an indirect effect on the pharmacokinetics of the parent compound, monitoring of the parent drug may be considered. Furthermore pharmacogenetic approaches considering uridine diphosphate (UDP) glucuronosyltransferases polymorphisms may become useful in the future to optimize therapy with drugs subject to glucuronidation.
Biomonitoring of inhaled complex mixtures - Ambient air, diesel exhaust and cigarette smoke
2005, Experimental and Toxicologic PathologyHuman biomonitoring comprises the determination of biomarkers in body-fluids, cells and tissues. Biomarkers are generally assigned to one of three classes, namely, biomarkers of exposure, effect or susceptibility. Since biomarkers represent steps in an exposure-disease continuum, their application in epidemiological studies (‘molecular epidemiology’) shows promise. However, to be a predictor of disease, a biomarker has to be validated. Validation criteria for a biomarker include intrinsic qualities such as specificity, sensitivity, knowledge of background in the population, existence of dose–response relationships, degree of inter- and intra-individual variability, knowledge of the kinetics, confounding and modifying factors. In addition, properties of the sampling and analytical procedures are of relevance, including constraints and non-invasiveness of sampling, stability of sample as well as simplicity, high sensitivity, specificity and speed of the analytical method. It is of particular importance to prove by suitable studies that the biomarker of exposure indicates the actual exposure, the biomarker of effect strongly predicts the actual risk of disease and the biomarker of susceptibility actually modifies the risk. Biomonitoring of the exposure to complex mixtures such as polluted ambient air, diesel exhaust or tobacco smoke is a particular challenge since these exposures have many constituents in common and many people were exposed to more than one of these mixtures. Data on the exposure to polycyclic aromatic hydrocarbons (PAH) and benzene from ambient air, diesel exhaust and tobacco smoke will be presented. In addition, some source-specific biomarkers such as nitro-arenes and nicotine metabolites as well as their application in population groups will be discussed.
The second part of the presentation addresses the application of biomarkers for assessing so called ‘potentially reduced exposure products’ (PREPs). According to a recent report of the Institute of Medicine (USA), “reducing risk of disease by reducing exposure to tobacco toxicants is feasible” and “surrogate biological markers that are associated with tobacco-related diseases could be used to offer guidance as to whether or not PREPs are likely to be risk-reducing.” In general, the same validation criteria apply as discussed above. In addition, it is suggested that a panel of biomarkers should be used, representing both smoke phases (gas and particulate phase) and the various chemical classes of smoke constituents (e.g., carbonyls, benzene, PAH, tobacco-specific nitrosamines, aromatic amines). Also, a panel of biomarkers of effect should cover the major known adverse effects of smoking (e.g., oxidative stress, inflammatory processes, lipid peroxidation, lipometabolic disorders, mutagenic effects). Biomarkers of nicotine and carbon monoxide uptake are of interest for evaluating the smoking and inhalation behavior, respectively. Finally, suitable study designs for evaluating PREPs are discussed.
It is concluded that suitable biomarkers for assessing the exposure to complex mixtures such as ambient air, diesel exhaust and tobacco smoke as well as for evaluating the exposure-reducing properties of PREPs are already available. Future efforts should focus on the development and validation of biomarkers of effect.
4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7
2000, Journal of Biological ChemistryIt is suggested that formation of more polar metabolites of all-trans-retinoic acid (atRA) via oxidative pathways limits its biological activity. In this report, we investigated the biotransformation of oxidized products of atRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4-OH-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4-OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidation. Glucuronidation of these retinoids by human liver microsomes and human recombinant UDP-glucuronosyltransferases (UGTs) was characterized and compared with the glucuronidation of atRA. The human liver microsomes glucuronidated 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, respectively. Analysis of the glucuronidation products showed that the hydroxyl-linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as opposed to the formation of the carboxyl-linked glucuronide with atRA, 4-oxo-RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to those found in human liver microsomes. We therefore postulate that this human isoenzyme, which is expressed in human liver, kidney, and intestine, plays a key role in the biological fate of atRA. We also propose that atRA induces its own oxidative metabolism via a cytochrome P450 (CYP26) and is further biotransformed into glucuronides via UGT-mediated pathways.
Cancer chemoprevention from the food-borne carcinogen 2-amino-1-methyl- 6-phenylimidazol[4,5-b]pyridine: Reconsideration of the evidence
1997, Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisEnzymes of phase I (cytochromes P450) and phase II (UDP [uridine diphosphate]-glucuronosyltransferases) of drug metabolism are targets of autoimmunity in the following chronic liver diseases of different etiology: 1)autoimmune hepatitis (AIH); 2) hepatitis associated with the autoimmune polyendocrine syndrome type 1 (APS-1); 3) virus-induced autoimmunity; and 4) drug-induced hepatitis. AIH is diagnosed by the following: the absence of infection with hepatitis viruses; the presence of a threshold of relevant factors, including circulating autoantibodies, hypergammaglobulinemia, female sex (female/male ratio 4:1), human leukocyte antigen (HLA) B8, DR3, or DR4; and benefit from immunosuppression. Patients with autoimmune hepatitis type 2 (AIH-2) are characterized by antibodies directed against liver and kidney microsomes, by an early onset of autoimmune hepatitis, which is a more aggressive course of the disease, and by a higher prevalence of autoimmunity directed against other organs. The major target of autoimmunity in patients with AIH-2 is cytochrome P450 2D6. Epitope mapping experiments revealed four short linear epitopes on cytochrome P450 2D6, recognized by liver/kidney microsomal autoantibodies type 1 (LKM-1) in patients with AIH-2. In addition, about 10% of the patient sera contain autoantibodies that detect a conformational epitope on UDP-glucuronosyltransferases (UGTs) of family 1. Presently, LKM-1 autoantibodies are used as diagnostic markers for AIH-2. It is unclear whether these autoantibodies have a pathogenetic role. Hepatitis is found in some patients with APS-1. Presumably this also is an autoimmune liver disease. APS-1 patients with hepatitis may develop autoantibodies directed against microsomal P450 enzymes of the liver; however, these autoantibodies do not recognize cytochrome P450 2D6, but they do recognize cytochrome P450 1A2. Autoimmunity in patients with APS-1 usually is directed against several organs simultaneously, and several organ specific autoantibodies may exist. Interestingly, APS-1 patients may produce various anti-cytochrome P450 antibodies. In addition to the hepatic anti-cytochrome P450, 1A2 autoantibodies are directed against steroidogenic cytochromes P450, namely P450 c21, P450 scc, and P450 c17. These autoantibodies correlate with adrenal and ovarian failure and often these steroidal cell autoantibodies precede the manifestation of adrenal or ovarian dysfunction. Whether anti-P450 1A2 autoantibodies have a similar predictive value is not yet known. LKM autoantibodies are further found in association with chronic hepatitis C and D. In chronic hepatitis C, the major target of LKM autoantibodies is cytochrome P450 2D6. Predominantly, conformational epitopes are recognized by LKM-1 sera of patients with chronic hepatitis C. In 13% of patients with chronic hepatitis D, LKM-3 autoantibody is detectable. The target proteins are UGTs of family 1 and in a minority of sera UGTs of family 2. The epitopes are conformational. All hepatic diseases discussed earlier have in common that autoimmunity, which is directed against enzymes of drug metabolizing multigene families. Each disease is characterized by a specific pattern of autoantibodies, with apparently little overlap. For example, LKM-1 autoantibodies, which are directed against P450 2D6, seem to overlap between AIH and chronic hepatitis C. However, a close examination of these autoantibodies shows differences between LKM-1 autoantibodies from patients with chronic hepatitis C and with AIH. In AIH, LKM autoantibodies are more homogenous, titers are higher, and major autoepitopes on cytochrome P450 2D6 are small and linear. LKM autoantibodies in viral hepatitis C are more heterogeneous and there are multiple epitopes, many of which are conformational. These differences indicate the different mechanisms that are involved in the generation of autoimmunity. (ABSTRACT TRUNCATED) (Hepatology 1997 Oct;26(4):1054-66)
Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat
1997, Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisThe mutagenic heterocyclic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), is a pyrolysis product in cooked foods that has been shown to be a rat colon carcinogen and has been implicated in the etiology of human colon cancer. In order to identify chemoprotection strategies that could be carried out in humans, a pilot study was conducted in which PhIP–DNA-adduct levels were quantified in the colons of male F344 rats that had been subjected to 16 different putative chemoprotection regimens, followed by a gavage of PhIP (50 mg/kg) and sacrifice 24 h later. The 16 treatments (Oltipraz, benzylisothiocyanate, diallyl sulfide, garlic powder, ethoxyquin, butylated hydroxyanisole, glutathione, indole-3-carbinol, α-angelicalactone, kahweol/cafestol palmitates, quercetin, green tea, black tea, tannic acid, amylase-resistant starch, and physical exercise) comprised sulfur-containing compounds, antioxidants, flavonoids, diterpenes, polyphenols, high dietary fiber, etc. The strongest inhibition of PhIP–DNA adduct formation in the colon was observed upon pretreatment with black tea, benzylisothiocyanate, and a mixture (1:1) of kahweol:cafestol palmitates, which resulted in 67, 66, and 54% decreases in colon PhIP–DNA adduct levels, as compared with controls. Preliminary studies on their mechanism of action indicated that only kahweol:cafestol caused a substantial induction of glutathione S-transferase isozymes (GSTs) that are thought to be important in the detoxification of PhIP. Notably, this induction occurred in the liver rather than in the colon.