Disease relevance of Cyp4d2

• Relation between the somatic toxicity of dimethylnitrosamine and a genetically determined variation in the level and induction of cytochrome P450 in Drosophila melanogaster [1].

High impact information on Cyp4d2

• Using the Somatic Mutation And Recombination Test (SMART) we have demonstrated that transgenic larvae expressing the P450 are hypersensitive to the anticancer drug cyclophosphamide, a procarcinogenic substrate which is activated by the enzyme [2].
• In this study we have used precise genetic mapping to identify a mechanism of lufenuron resistance: the overexpression of the cytochrome P450 gene Cyp12a4 [3].
• Shade is the Drosophila P450 enzyme that mediates the hydroxylation of ecdysone to the steroid insect molting hormone 20-hydroxyecdysone [4].
• The present data show that the wild-type genes of two members of the Halloween family of embryonic lethals, disembodied (dib) and shadow (sad), code for mitochondrial cytochromes P450 that mediate the last two hydroxylation reactions in the ecdysteroidogenic pathway in Drosophila, namely the C22- and C2-hydroxylases [5].
• Five different enzymatic activities, catalyzed by both microsomal and mitochondrial cytochrome P450 monooxygenases (CYPs), are strongly implicated in the biosynthesis of ecdysone (E) from cholesterol [5].

Biological context of Cyp4d2

• Cluster of cytochrome P450 genes on the X chromosome of Drosophila melanogaster [6].
• Expression and down-regulation of cytochrome P450 genes of the CYP4 family by ecdysteroid agonists in Spodoptera littoralis and Drosophila melanogaster [7].
• Previous studies have suggested that production of 20-hydroxyecdysone in Drosophila and other arthropods involves a series of cytochrome P450 catalyzed hydroxylations of cholesterol [8].
• The Drosophila disembodied gene controls late embryonic morphogenesis and codes for a cytochrome P450 enzyme that regulates embryonic ecdysone levels [8].
• The genetic map of the distribution of D. melanogaster P450 genes shows (a) the absence of P450 genes on the chromosome 4 and Y, (b) more than half of the P450 genes are found on chromosome 2, and (c) the largest cluster contains nine genes [9].

Anatomical context of Cyp4d2

• This is the first indication of a specific P450 expressed in the central nervous system of Drosophila, and the putative function of the corresponding enzyme is discussed [10].
• Furthermore, analysis of c/ebp beta-deficient mice shows that mutant animals are defective in expression of a murine CYP2D5 homolog in hepatic cells, confirming the selective ability of C/EBP beta to activate this liver-specific P-450 gene in vivo [11].
• In contrast, increases in the rate of BP turnover per molecule of cytochrome P-450, intensity of the hemoprotein band with apparent molecular weight 56,000 and the yield of BP 7,8-dihydrodiol and 9,10-dihydrodiol occurred only in microsomes of BP-pretreated 364yv flies but not of Turku ones [12].
• Feeding of these compounds in combination with the inhibition of cytochrome P-450 by 1-phenylimidazole (PhI) allowed sufficient quantities of the mutagen to reach the gonads and to produce significant genetic damage [13].
• These results indicate that the fat body participates in the P450-mediated metabolism of excess furanocoumarins unmetabolized by the midgut [14].

Associations of Cyp4d2 with chemical compounds

• However, there is some controversy as to how the second step of the reaction, from NHA to NO and L-citrulline, occurs within the P450 domain of NOS [15].
• A genetic variation between the strains was observed after phenobarbital (PB) treatment in the content of cytochrome P-450 and in the various enzyme activities, varying from non-responsiveness to a 4- to 5-fold increase [16].
• Dimethylnitrosamine demethylase, a P-450 enzyme, is a component of band b [17].
• It is of special interest that adults and larvae possess cytochrome P-450-dependent activation systems able to metabolize most promutagens, e.g., nitrosamines, aflatoxins, pyrrolizidine alkaloids, safrole, etc [18].
• The principal active metabolite of cyclophosphamide, phosphoramide mustard, is extensively de-activated by enzymes that can be inhibited by 1-phenylimidazole (PhI), presumably cytochrome P-450 (EC 1.14.14.1), but not by those blocked by MAO inhibitors [19].

Other interactions of Cyp4d2

• CYP4D2 lies 20 kb proximal to the previously described CYP4D1 gene (Gandhi et al., 1992) [6].
• In this report, we show that the disembodied (dib) locus of Drosophila codes for a P450-like sequence [8].
• Five of the ten PCR products of genomic DNA were shown to contain a short (60-79 bp) intron at the same position as introns in the Drosophila CYP4D2 and CYP4E1 genes [20].

Analytical, diagnostic and therapeutic context of Cyp4d2

• Sequence alignments were used to draw phylogenetic trees and to analyze the intron-exon organization of each functional P450 gene [9].
• A novel cytochrome P450 was isolated from Drosophila melanogaster by PCR strategy with primers deduced from the crayfish Orconectes limosus CYP4C15 sequence, which is supposed to be involved in ecdysteroid biosynthesis [10].
• Twelve cytochrome P450 cDNA fragments were cloned from Drosophila melanogaster by reverse transcriptase/PCR (RT/PCR) using degenerate oligonucleotide primers [21].
• P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature [22].
• Although the chromosome 2 locus was not associated with a significant increase in cytochrome P-450 content, SDS polyacrylamide gel electrophoresis of microsomal proteins detected increased silver staining of a polypeptide having a relative molecular mass (Mr) of about 52,000 [23].

References