Compound lipophilicity is of key importance to P450 binding affinity and enzyme selectivity. Here, lipophilicity is discussed with reference to the human drug-metabolizing P450 enzymes of families CYP1, CYP2 and CYP3. From an extensive compilation of log P values for P450 substrates, and by analysis of relationships between partitioning energy and substrate-binding free energy, the relevance of...

The tobacco specific carcinogen N'-nitrosonornicotine (NNN), is believed to be a causative agent for esophageal cancer in smokers. NNN requires metabolic activation to exert its carcinogenic potential. Metabolism occurs through cytochrome P450 (P450) catalyzed 2'- and 5'-hydroxylation, which generates unstable metabolites that decompose to 4-hydroxy-1-(3-pyridyl)-1-butanone ('keto alcohol') and...

Since its discovery in the 1980s, the fatty acid hydroxylase flavocytochrome P450 (cytochrome P450) BM3 (CYP102A1) from Bacillus megaterium has been adopted as a paradigm for the understanding of structure and mechanism in the P450 superfamily of enzymes. P450 BM3 was the first P450 discovered as a fusion to its redox partner--a eukaryotic-like diflavin reductase. This fact fuelled the interest...

The nitrogenous pi -acceptor ligand 4-cyanopyridine (4CNPy) exhibits reversible ligation to ferrous heme in the flavocytochrome P450 BM3 (Kd=1.8 microm for wild type P450 BM3) via its pyridine ring nitrogen. The reduced P450-4CNPy adduct displays unusual spectral properties that provide a useful spectroscopic handle to probe particular aspects of this P450. 4CNPy is competitively displaced upon...

Olopatadine, a new histamine H(1) receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety. Some compounds containing a similar alkylamino group form a cytochrome p450 (p450) -iron (II)-nitrosoalkane metabolite complex [metabolic intermediate complex (MIC)], thereby causing quasi-irreversible inhibition of the p450. There was concern that olopatadine might also form MI...

There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for ...

Cytochrome P450 monooxygenases (P450s) are heme-thiolate proteins distributed across the biological kingdoms. P450s are catalytically versatile and play key roles in organisms primary and secondary metabolism. Identification of P450s across the biological kingdoms depends largely on the identification of two P450 signature motifs, EXXR and CXG, in the protein sequence. Once a putative protein h...

Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolized by cytochrome P450s (P450s) through either a dearylation reaction to form an inactive metabolite, or through a desulfuration reaction to form an active oxon metabolite, which is a potent cholinesterase inhibitor. This study investigated th...

The world's most expensive wood, sandalwood (Santalum album L.), requires a stringent mass-propagation technique to prevent future scarcity. Plant tissue culture is an efficient method that regenerates the whole plant from single cell on hormone-based growth medium. To efficiently regulate formation of plants, it important understand developmental organogenesis pathways (i.e., direct and indire...

The demethylation of carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosomethylaniline (NMA) is catalyzed by purified rat liver cytochromes P450 2B1 and 2B2 reconstituted with NADPH-P450 reductase and dilauroylphosphatidylcholine. A molar P450 to reductase ratio of about 1.0 is the most appropriate for the catalysis. NMA is a better substrate for both P450 enzymes than NDMA, with K(m) value...