Annual Review of Pharmacology and Toxicology
1545-4304
0362-1642
Mỹ
Cơ quản chủ quản: ANNUAL REVIEWS , Annual Reviews Inc.
Lĩnh vực:
PharmacologyToxicology
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Thông tin về tạp chí
The Annual Review of Pharmacology and Toxicology, in publication since 1961, covers the significant developments in the fields of pharmacology and toxicology, including receptors, transporters, enzymes, and chemical agents; drug development science; systems such as the immune system, central and autonomic nervous systems, gastrointestinal system, cardiovascular system, endocrine system, and pulmonary system; and special topics.
Các bài báo tiêu biểu
CYTOCHROME P-450 3A4: Regulation and Role in Drug Metabolism ▪ Abstract Cytochrome P-450 (P-450) 3A4 is the most abundant P-450 expressed in human liver and small intestine. P-450 3A4 contributes to the metabolism of approximately half the drugs in use today, and variations in its catalytic activity are important in issues of bioavailability and drug-drug interactions. The gene is known to be inducible by barbiturates, glucocorticoids, and rifampicin in humans and in isolated hepatocytes, although the mechanism remains unclear. The 5′-untranslated region includes putative basal transcription element, hepatocyte nuclear factor, p53, AP-3, glucocorticoid regulatory element, pregnane X receptor, and estrogen receptor element sequences. Recently, the GRE element has been shown to act in a classic glucocorticoid response. Several issues remain to be resolved regarding the catalytic activity of the P-450 3A4 protein, including rate-limiting steps and the need for cytochrome b5 , divalent cations, and acidic phospholipid systems for optimal activity. Another issue involves the basis of the homotropic and heterotropic cooperativity seen with the enzyme. The in vivo significance of these findings remains to be further established. In addition to more basic studies on P-450 3A4, several areas of practical interest to the pharmaceutical industry require development.
Tập 39 Số 1 - Trang 1-17 - 1999
REGULATION AND INHIBITION OF PHOSPHOLIPASE A<sub>2</sub> ▪ Abstract In recent years, there has been great interest in the study of phospholipid metabolism in intact cell systems. Such an interest arises mainly from the discovery that cellular membrane phospholipids serve not only in structural roles, but are also reservoirs of preformed second messenger molecules with key roles in cellular signaling. These second messenger molecules are generated by agonist-induced activation and secretion of intracellular and extracellular phospholipases, respectively, i.e. enzymes that cleave ester bonds within phospholipids. Prominent members of the large collection of signal-activated phospholipases are the phospholipase A2 s. These enzymes hydrolyze the sn-2 ester bond of phospholipids, releasing a free fatty acid and a lysophospholipid, both of which may alter cell function. In addition to its role in cellular signaling, phospholipase A2 has recently been recognized to be involved in a wide number of pathophysiological situations, ranging from systemic and acute inflammatory conditions to cancer. A growing number of pharmacologic inhibitors will help define the role of particular phospholipase A2 s in signaling cascades.
Tập 39 Số 1 - Trang 175-189 - 1999
METALLOTHIONEIN: An Intracellular Protein to Protect Against Cadmium Toxicity ▪ Abstract Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a “storehouse” for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two proposed functions but strongly support its function in protecting against Cd toxicity. Repeated administration of Cd to MT-null mice results in nephrotoxicity at one tenth the dose that produces nephrotoxicity in control mice. Human studies indicate that 7% of the general population have renal dysfunction from Cd exposure. Therefore, if humans did not have MT, “normal” Cd exposure would be nephrotoxic to humans. Thus, it appears that during evolution, the ability of MT to protect against Cd toxicity might have taken a more pivotal role in the maintenance of life processes, as compared with its other proposed functions (i.e. storehouse for zinc and free radical scavenger).
Tập 39 Số 1 - Trang 267-294 - 1999
Regulatory Mechanisms Controlling Gene Expression Mediated by the Antioxidant Response Element The expression of genes encoding antioxidative and Phase II detoxification enzymes is induced in cells exposed to electrophilic compounds and phenolic antioxidants. Induction of these enzymes is regulated at the transcriptional level and is mediated by a specific enhancer, the antioxidant response element or ARE, found in the promoter of the enzyme's gene. The transcription factor Nrf2 has been implicated as the central protein that interacts with the ARE to activate gene transcription constitutively or in response to an oxidative stress signal. This review focuses on the molecular mechanisms whereby the trancriptional activation mediated by the interaction between the ARE and NF-E2-related factor 2 (Nrf2) is regulated. Recent studies suggest that the sequence context of the ARE, the nature of the chemical inducers, and the cell type are important for determining the activity of the enhancer in a particular gene.
Tập 43 Số 1 - Trang 233-260 - 2003
Physiological Functions of Cyclic ADP-Ribose and NAADP as Calcium Messengers Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two Ca2+ messengers derived from NAD and NADP, respectively. Although NAADP is a linear molecule, structurally distinct from the cyclic cADPR, it is synthesized by similar enzymes, ADP-ribosyl cyclase and its homolog, CD38. The crystal structure of the cyclase has been solved and its active site identified. These two novel nucleotides have now been shown to be involved in a wide range of cellular functions including: cell cycle regulation in Euglena, a protist; gene expression in plants; and in animal systems, from fertilization to neurotransmitter release and long-term depression in brain. A battery of pharmacological reagents have been developed, providing valuable tools for elucidating the physiological functions of these two novel Ca2+ messengers. This article reviews these recent results and explores the implications of the existence of multiple Ca2+ messengers and Ca2+ stores in cells.
Tập 41 Số 1 - Trang 317-345 - 2001
Inhibition of Carcinogenesis by Tea Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.
Tập 42 Số 1 - Trang 25-54 - 2002
Neuropharmacology of Phencyclidine: Basic Mechanisms and Therapeutic Potential
Tập 30 Số 1 - Trang 707-750 - 1990
THE MAGIC BULLETS AND TUBERCULOSIS DRUG TARGETS ▪ Abstract Modern chemotherapy has played a major role in our control of tuberculosis. Yet tuberculosis still remains a leading infectious disease worldwide, largely owing to persistence of tubercle bacillus and inadequacy of the current chemotherapy. The increasing emergence of drug-resistant tuberculosis along with the HIV pandemic threatens disease control and highlights both the need to understand how our current drugs work and the need to develop new and more effective drugs. This review provides a brief historical account of tuberculosis drugs, examines the problem of current chemotherapy, discusses the targets of current tuberculosis drugs, focuses on some promising new drug candidates, and proposes a range of novel drug targets for intervention. Finally, this review addresses the problem of conventional drug screens based on inhibition of replicating bacilli and the challenge to develop drugs that target nonreplicating persistent bacilli. A new generation of drugs that target persistent bacilli is needed for more effective treatment of tuberculosis.
Tập 45 Số 1 - Trang 529-564 - 2005
14-3-3 Proteins: Structure, Function, and Regulation The 14-3-3 proteins are a family of conserved regulatory molecules expressed in all eukaryotic cells. A striking feature of the 14-3-3 proteins is their ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. This plethora of interacting proteins allows 14-3-3 to play important roles in a wide range of vital regulatory processes, such as mitogenic signal transduction, apoptotic cell death, and cell cycle control. In this review, we examine the structural basis for 14-3-3–ligand interactions, proposed functions of 14-3-3 in various signaling pathways, and emerging views of mechanisms that regulate 14-3-3 actions.
Tập 40 Số 1 - Trang 617-647 - 2000