Zaid Jayyosi

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Promotion of Colon Tumors in C57BL/6J-APCmin/+ Mice by Thiazolidinedione PPARγ Agonists and a Structurally Unrelated PPARγ Agonist

Thiazolidinedione PPARγ agonists (troglitazone and rosiglitazone) were previously shown to promote colon tumor formation in C57BL/6JAPC min/+ mice, a model for human familial adenomatous polyposis. This study was conducted to determine if another thiazolidinedione PPARγ agonist, pioglitazone, and a PPARγ agonist structurally unrelated to the thiazolidinedione family, NID525, (a tetrazole-substituted phenoxymethylquinolone), would also promote colon tumors in this mouse model. Mice were treated in-feed with the thiazolidinediones troglitazone (150 mg/kg/day), rosiglitazone (20 mg/kg/day), or pioglitazone (150 mg/kg/day), or with NID525 (150 mg/kg/day) for 8 weeks. An increased incidence in colon tumors compared to controls was observed for all of the thiazolidinedione-treated groups as well as the NID525-treated group. These results indicate that the tumor-promoting effect of PPAR γ agonists in the colon of C57BL/6J-APCmin/+ mice is likely related to the pharmacological activity of this group of drugs and not the thiazolidinedione structure.

Catalytic and immunochemical characterization of cytochrome P450 isozyme induction in dog liver.

The purpose of this study was to characterize hepatic cytochrome P450 induction in the dog by phenobarbital, beta-naphthoflavone, dexamethasone, and isoniazid using catalytic activities and Western blots with antibodies prepared against rat cytochrome P450 isozymes. Male beagle dogs were treated with phenobarbital (10 mg/kg for 2 days and 30 mg/kg for the following 5 days), beta-naphthoflavone (50 mg/kg for 5 days), or isoniazid (10 mg/kg for 2 days and 30 mg/kg for the following 5 days). Female beagle dogs were treated with dexamethasone (50 mg/kg for 5 days). Increases in the liver/body weight ratio were observed after treatment of dogs with phenobarbital (133% of control) and dexamethasone (153%). Total cytochrome P450 content was increased as a percentage of control after treatment with phenobarbital (264%) and (3-naphthoflavone (186%), while it slightly decreased after treatment with isoniazid (54%) and dexamethasone (71%). Dog liver microsomes hydroxylated testosterone mainly at the 6-beta and 16-alpha positions but also at the 6-alpha-, 15-beta-, 15-alpha-, 16-beta-, 18-, 2-beta-, and 17-positions. There were no sex differences in terms of regio-selectivity of testosterone metabolism between control male and female dogs. Treatment of dogs with phenobarbital produced increases in 6-beta- (184%), 16-alpha- (379%), 16-beta- (210%), 18- (195%), and 2-beta-testosterone (203%) hydroxylase and pentoxyresorufin 0-dealkylase (651%) activities. On Western blots, phenobarbital treatment produced induction of P450 3A- and 2B1-related proteins. Although treatment with dexamethasone resulted in a large increase in liver weight, no significant increase in P450 3A-related protein or 6-beta-hydroxylase activity was detected. However, dexamethasone and isoniazid treatment produced slight increases in chlorzoxazone hydroxylase activity. Treatment with isoniazid induced a P450 2E1-related protein. Treatment with (beta-naphthoflavone produced increases that were 689 and 357% of control in ethoxyresorufin 0-deethylase and chlorzoxazone hydroxylase activities, respectively. Beta-Naphthoflavone treatment increased the amount of two proteins immunochemically related to the cytochrome P450 1A subfamily. Thus, although generally similar to other species, the response of the dog to cytochrome P450 inducers differs significantly from the rat and human in some cases.

The Hepatic Transcriptome as a Window on Whole-Body Physiology and Pathophysiology

Transcriptomics can be a valuable aid to pathologists. The information derived from microarray studies may soon include the entire transcriptomes of most cell types, tissues and organs for the major species used for toxicology and human disease risk assessment. Gene expression changes observed in such studies relate to every aspect of normal physiology and pathophysiology. When interpreting such data, one is forced to look “far from the lamp post,” and in so doing, face one’s ignorance of many areas of biology. The central role of the liver in toxicology, as well as in many aspects of whole-body physiology, makes the hepatic transcriptome an excellent place to start your studies. This article provides data that reveals the effects of fasting and circadian rhythm on the rat hepatic transcriptome, both of which need to be kept in mind when interpreting large-scale gene expression in the liver. Once you become comfortable with evaluating mRNA expression profiles and learn to correlate these data with your clinical and morphological observations, you may wonder why you did not start your studies of transcriptomics sooner. Additional study data can be viewed at the journal website at . Two data files are provided in Excel format, which contain the control animal data from each of the studies referred to in the text, including normalized signal intensity data for each animal (n = 5) in the 6-hour, 24-hour, and 5-day time points. These files are briefly described in the associated ‘Readme’ file, and the complete list of GenBank numbers and Affymetrix IDs are provided in a separate txt file. These files are available at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. Click on the issue link for 33(1), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through .

Complementary Roles for Toxicologic Pathology and Mathematics in Toxicogenomics, With Special Reference to Data Interpretation and Oscillatory Dynamics

Toxicogenomics is an emerging multidisciplinary science that will profoundly impact the practice of toxicology. New generations of biologists, using evolving toxicogenomics tools, will generate massive data sets in need of interpretation. Mathematical tools are necessary to cluster and otherwise find meaningful structure in such data. The linking of this structure to gene functions and disease processes, and finally the generation of useful data interpretation remains a significant challenge. The training and background of pathologists make them ideally suited to contribute to the field of toxicogenomics, from experimental design to data interpretation. Toxicologic pathology, a discipline based on pattern recognition, requires familiarity with the dynamics of disease processes and interactions between organs, tissues, and cell populations. Optimal involvement of toxicologic pathologists in toxicogenomics requires that they communicate effectively with the many other scientists critical for the effective application of this complex discipline to societal problems. As noted by Petricoin III et al (Nature Genetics 32, 474-479, 2002), cooperation among regulators, sponsors and experts will be essential for realizing the potential of microarrays for public health. Following a brief introduction to the role of mathematics in toxicogenomics, “data interpretation” from the perspective of a pathologist is briefly discussed. Based on oscillatory behavior in the liver, the importance of an understanding of mathematics is addressed, and an approach to learning mathematics “later in life” is provided. An understanding of pathology by mathematicians involved in toxicogenomics is equally critical, as both mathematics and pathology are essential for transforming toxicogenomics data sets into useful knowledge.

Subchronic toxicity studies with the leukotriene D4 antagonist RG 12525.

Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.