Human cytochrome P450 1A2 involvement in the formation of reactive metabolites from a species-specific hepatotoxic pyrazolopyrimidine derivative, 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine

Chemical Research in Toxicology
Shunji KuribayashiH Yamazaki

Abstract

5-n-Butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine) (OT-7100) is a pyrazolopyrimidine derivative with potential analgesic effects. Exclusively limited elevations in serum levels of aspirate- and alanine-aminotransferase were abnormally observed in a clinical study, in contrast to no toxicological potential to experimental animals. The aim of this study was to clarify the mechanism responsible for species-specific hepatotoxicity of this model compound. OT-7100 was primarily metabolized to a carboxylic acid derivative and an amino derivative (5-n-butyl-pyrazolo[1,5-a]pyrimidine, M-5) by hydrolysis in humans and rats. In human liver, pyrazolo[1,5-a]pyrimidine derivative M-5 was further metabolized to mainly M-23OH (a C-3-position hydroxyl derivative, 3-hydroxy-5-n-butyl-pyrazolo[1,5-a]pyrimidine). Studies with recombinant cytochrome P450s (P450s), correlation analysis using a panel of human liver microsomes as well as immunoinhibition with anti-P450 antibodies collectively suggested that human liver microsomal P450 1A2 preferentially metabolized M-5 to predominantly M-23OH. Human liver microsomes were capable of activating M-5 to a covalently bound metabolite faster than rat liver microsomes: reduced glutathione p...Continue Reading

References

Jun 1, 1989·Archives of Biochemistry and Biophysics·J L RaucyM Black
Oct 1, 1984·Biochemical Pharmacology·J O MinersD J Birkett
Apr 22, 1993·Biochemical Pharmacology·K E ThummelJ T Slattery
Mar 28, 2002·The Journal of Toxicological Sciences·Charles RothwellFelix A de la Iglesia
Jun 21, 2002·Toxicological Sciences : an Official Journal of the Society of Toxicology·J R HermanF A de la Iglesia
Jun 17, 2003·Chemical Research in Toxicology·Martyn T Smith
Aug 2, 2003·The New England Journal of Medicine·William M Lee
Nov 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Laura P JamesJack A Hinson
Feb 18, 2004·Chemical Research in Toxicology·Elizabeth M JoshiTimothy L Macdonald
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·B Kevin ParkDominic P Williams
May 11, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S KuribayashiT Kamataki

❮ Previous
Next ❯

Citations

May 16, 2015·Beilstein Journal of Organic Chemistry·Marina V GoryaevaViktor I Saloutin
May 11, 2018·Chemical Research in Toxicology·Alf Claesson, Alexander Minidis

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.