Current Status of the Cytosolic Sulfotransferases in the Metabolic Activation of Promutagens and Procarcinogens Pp.1-30
[Abstract] [Full Text Article]
[Abstract] [Full Text Article]
Xenobiotic-CoA Ligases: Kinetic and Molecular
Characterization Pp.49-66
[Abstract] [Full Text Article]
Abstracts
[Back
to top] Current Status of the Cytosolic Sulfotransferases in the Metabolic
Activation of Promutagens and Procarcinogens
Erden Banoglu
Cytosolic sulfotransferases (SULT) catalyze the sulfation of structurally diverse drugs, endogenous compounds and xenobiotics. These reactions involve the transfer of a sulfuryl group from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to the hydroxyl/amino groups of acceptor molecules. Although sulfate conjugation is generally considered as a detoxication pathway producing more water-soluble and often less toxic metabolites, sulfation of certain classes of compounds produce sufficiently electrophilic metabolites that can covalently bind to cellular macromolecules, DNA and RNA. The important roles of electrophilic sulfate ester metabolites in the metabolic activation, mutagenicity and ultimate carcinogenicity of many xenobiotics have been considerably elucidated. Examples include the class of hydroxymethyl polycyclic aromatic hydrocarbons, allylic alcohols, N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines. Results obtained by many scientists during the last two decade correlate with a hypothesis that electrophilic sulfate esters may be the major ultimate carcinogenic forms of many, if not most, procarcinogens derived from benzylic/allylic alcohols and hydroxy arylamines. Careful analysis of these results suggest that the activities of human hydroxysteroid sulfotransferase (hHST), and a related form in rat liver, rat hydroxysteroid sulfotransferase a (STa), as well as aryl sulfotransferases both from rat and human liver, account for a substantial portion of the activation of benzylic/allylic alcohols in these species. Moreover, aryl sulfotransferases have also been indicated as the responsible SULT family in the bioactivation of hydroxy arylamines in the liver of different species including human. Molecular cloning of the individual sulfotransferases and expression of these individual forms in heterologous expression systems have allowed us to better understand the role of SULTs in the bioactivation of different procarcinogens and the form of sulfotransferase involved in their bioactivation. Additional structure-activity studies with homogeneous forms of rat liver STa and AST IV have also yielded comparative insight into some of the parameters important in recognition of substrates and inhibitors by these enzymes.
[Back to top] Effective Prodrug Liposome and Conversion to Active Metabolite
Y.
Sadzuka
Some antitumor agents encapsulated in liposomes have been used clinically. However, the usefulness of liposomes is limited to the liposomalization of active compounds. Irinotecan hydrochloride (CPT-11) is a prodrug of closed lactone ring form of SN-38, which is an active metabolite with antitumor activity and side toxicity. The plasma concentrations of closed CPT-11 and SN-38 increased with the liposomalization, and their blood circulation was prolonged by the polyethyleneglycol (PEG) modification. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of closed CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. The closed/total ratio of SN-38 in the tumors of the liposomes group was greater than that of the CPT-11 solution group. Namely, SN-38 was thought to be generated in intact liposomes containing CPT-11. The generation of SN-38 in the liposomal membrane was shown after the incubation of liposome containing CPT-11 with carboxylesterase. It is therefore considered that part of CPT-11 is converted to SN-38 in intact liposomes. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased to depend on the closed SN-38 concentrations in the bile by liposomalization. Although the liposomes induce the improved tissue distribution of the prodrug, the tissue distribution of active metabolites do not always improve. However, CPT-11 entrapped liposome was useful.
[Back to top] Xenobiotic-CoA Ligases: Kinetic and Molecular Characterization
K.
M. Knights and C. J. Drogemuller
This review focuses primarily on the mammalian medium and
long-chain fatty acid coenzyme A ligases that have been implicated in the
metabolism of xenobiotic carboxylic acids such as pesticides, arylpropionate
non steroidal anti-inflammatory drugs and the hypolipidaemic clofibrate and its
congeners. Evidence of multiplicity of mitochondrial and microsomal enzymes and
their respective substrate/inhibitor profiles are discussed. For completeness,
where appropriate, details of non-substrate inhibitors have also been included.
Although knowledge is limited at present with respect to the medium-chain
enzymes, aspects of regulation particularly the in vivo, in vitro role of peroxisome proliferators and current
knowledge of the molecular biology of the long-chain fatty acid CoA ligase
superfamily are documented. Additionally, alignment of thirteen cloned
mammalian fatty acid CoA ligases using criteria established for the CYP and UGT
superfamilies has enabled construction of a phylogenetic tree that clearly defines
three families. Catalytic data are still limited and the xenobiotic
substrate/inhibitor profiles of the recombinant proteins are incomplete.
Finally, with increasing recognition of the importance of fatty acyl-CoA esters
as physiological regulators of cell function including gene expression, the
review concludes with a discussion of the metabolic fate and toxicity of
xenobiotic acyl-CoA esters.
[Back to top] Mechanisms of Inhibitory
and Regulatory Effects of Methylenedioxyphenyl Compounds on Cytochrome P450-Dependent
Drug Oxidation
Michael
Murray
Cytochrome P450 (CYP) enzymes catalyse the oxidative conversion of drugs and other lipophilic compounds to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidation by specific CYPs whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs.
Methylenedioxyphenyl (MDP) compounds have been widely employed as commercially important pesticide synergists and a number of derivatives are found in oils and spices. MDP compounds are of considerable toxicological significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivatives produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clinical importance that possess the MDP structural feature, the synthesis and preclinical evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compounds it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chemical mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clinical value of new drugs.
[Back to top] Turnover Studies on
Cardiac Natriuretic Peptides: Methodological, Pathophysiological and Therapeutical
Considerations
Aldo
Clerico, Giorgio Iervasi, Alessandro Pilo
Cardiac natriuretic peptide hormones (ANP and BNP) are synthesized and secreted by the heart, producing several biological effects, such as natriuresis, vasorelaxation, hypotension, and neuromodulation. Extensive studies conducted in both animals and humans have documented that cardiac natriuretic peptides (CNPs) are secreted into the circulatory system via the coronary sinus into the right atrium, and then rapidly degraded and removed from the blood by plasma proteases and specific clearance receptors. Usually, studies of CNPs kinetics have been carried out following an experimental protocol in which labeled or unlabeled hormone is administered (by constant infusion or bolus injection) and the corresponding concentration of the hormone is measured in peripheral venous blood. However, when a uniform intravascular concentration throughout artero-venous vessels is lacking due to the very rapid clearance of the substance being studied (such as CNPs), the classical compartmental or non compartmental approach may not be suitable for interpreting the experimental data. In this case, a more physiological circulatory model, which does not assume a uniform intravascular distribution of the hormone and comprises several anatomo-functional blocks arranged in a series and supplied by the same flow (cardiac ouput) should be adopted. Different experimental designs (infusion or bolus injection) as well as multiple sampling sites (aorta and pulmonary artery, inferior vena cava, femoral vein) were used in ANP kinetic studies. Using a circulatory approach, ANP has been demonstrated to be rapidly distributed and degraded; in healthy subjects about 50% of ANP secreted into the right atrium is extracted by the peripheral tissues during the first pass throughout the body. Since CNPs have important fluid-volume regulatory features, it has been postulated that they also play a key role in volume homeostasis in several pathophysiological states, such as congestive heart failure. Indeed, a markedly altered degradation and distribution of ANP in patients with cardiac failure who show a resistance to its natriuretic effects, even in those on the early stage of clinical disease, whose CNPs plasma levels are in the normal range, have been demonstrated. Recent studies indicate that some drugs, by inhibiting the degradation of CNPs by plasma proteases and can thus affect CNP kinetics, may be useful in the treatment of arterial hypertension and cardiac failure.