Current Medicinal Chemistry - Volume 16, Issue 21, 2009

Protein p53 is a key player in mitochondrial mediated apoptotic cell death and excess p53 activity has been implicated in many disease states such athrosclerosis, diabetes, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS, P. falciparum and S. typhimurium infections. Thus, chemical inhibitors of p53 activation might prove effective in suppressing diseases associated with excess p53 activity. Diverse chemical compounds are being synthesized and evaluated as potent inhibitors of p53 in many cell types. In this review, we have focused on the effects of apoptosis, which is involved in p53 protein and inhibition of p53 induced apoptosis. Peculiar features of p53 protein and its roles in various diseases are summarized along with important inhibitors developed in recent years.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that primarily binds and regulates oxidized low-density lipoprotein (LDL). Expression of LOX-1 is regulated by a feed-forward system stimulated by oxidized LDL (oxLDL), a major component of atherosclerosis. LOX-1 is a homodimer with a reactive backbone that can bind to a host of different ligands, including small molecules, and whole cells. LOX-1 is involved in many intercellular, intracellular, and molecular processes that are atherogenic. LOX-1 levels are elevated within atherosclerotic plaques and its expression is induced by proinflammatory cytokines. The ability of LOX-1 to bind many different ligands and control several atherogenic processes makes this receptor a likely vascular disease biomarker as well as an ideal choice for drug therapy aimed at preventing cardiovascular disease.

Lipopolysaccharides (LPS, endotoxins) belong to the strongest elicitors of the mammalian immune system due to the induction of a series of cytokines such as tumor-necrosis-factor-α (TNFα) in immunocompetent cells like mononuclear cells. Since the effects of LPS on human health may be pathologically at too high concentrations (e.g., septic shock syndrome), it is of uttermost importance to have a reliable assay for measuring the concentrations of endotoxins in vitro and in vivo (human body fluids). The activation of the clotting cascade from the horseshoe crab (Limulus polyphemus), the Limulus amoebocyte lysate test (LAL), has been the standard and most sensitive assay to detect bacterial endotoxins. However, there are restrictions with this test. It was found in some clinical trials that the results from the LAL test did not correlate with the presence of bacteremia due to Gram-negative organisms or with the mortality but correlated with the presence of fungal bloodstream infections. This resulted from the fact that the LAL assay does not only respond to bacterial endotoxins but is activated also by (1→3)-β-D-glucan. Furthermore, in extensive studies the structural requirements for activation of the LAL test were analyzed, and it was found that the LAL activity correlated with pyrogenicity but not with activation of the complement cascade. Furthermore, there was no correlation of the LAL activity with cytokine expression (for example tumor-necrosis-factor-α and interleulkins-1 and 6) in mononuclear cells when the 4/2 acyl chain pattern of enterobacterial lipid A was changed, or when the cytokine production induced by LPS from various different species in the whole blood assay was compared with the response from the LAL test. To clarify the questions raised by the different experimental findings, data from literature are summarized to get a more closer insight where the Limulus test confidentially monitors the endotoxicity of LPS and other compounds and where this is not the case, and which are the decisive epitopes for recognition of the LPS molecules. These data are very crucial for example in clinical tests, whether the LAL assay can reliably describe the effectivity of an antibacterial therapy.

CYP2D6 accounts for only a small percentage of total hepatic CYPs (<2%), but it metabolizes ∼25% of clinically used drugs (>100) with significant polymorphisms. A number of drugs acting on the central nervous system and cardiovascular system are substantially metabolized by CYP2D6. The enzyme also utilizes hydroxytryptamines and neurosteroids as endogenous substrates. In addition, CYP2D6 metabolizes procarcinogens and neurotoxins such as 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, and indolealkylamines. Typical CYP2D6 substrates are usually lipophilic bases with a planar hydrophobic aromatic ring and a nitrogen atom which can be protonated at physiological pH, but several atypical substrates such as spirosulfonamide and pactimibe do not contain a basic nitrogen atom. The structure of human CYP2D6 has been recently determined and shows the characteristic CYP fold as observed in other members of the CYP superfamily, with a well-defined active site cavity above the heme group with a volume of ∼540 Å3. CYP2D6 is largely uninducible by prototypical CYP inducers such as phenobarbital, rifampin and dexamethasone, but it is regulated by hepatocyte nuclear factor-4α, a nuclear receptor. CYP2D6 is subject to inhibition by a number of drugs and this may provide an explanation for numerous clinical drug interactions. CYP2D6 has an important role in drug development and it is a common practice for pharmaceutical industry nowadays to a great extent screen drug candidates early in development as possible CYP2D6 substrates and/or inhibitors and drop such candidates where they have alternatives. This candidate selection might eventually lead to a less prominent role of this enzyme in the future for drug metabolism and less interindividual variability in drug exposure and minimize potentially adverse drug interactions. Further studies are warranted to delineate the molecular mechanisms involved in the function and regulation of CYP2D6.