Mouse cytochrome P<sub>3</sub>-450: complete cDNA and amino acid sequence

Kimura, Shioko; Gonzalez, Frank J.; Nebert, Daniel W.

doi:10.1093/nar/12.6.2917

Cited by 59 publications

(16 citation statements)

References 41 publications

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“…It has also recently been observed (with one or two divergent residues) in the protein sequences derived from three distinct rabbit P450 cDNAs, one of which probably corresponds to LM-3b (25). The sequence of the tridecapeptide is substantially less, albeit significantly, conserved in the major cytochromes P-450 induced by 3-methylcholanthrene, P450c (26) and P-450d (27) in the rat and P1450 (28) and P3450 (23,28) in the mouse. The high conservation within the various P-450 genes of the tridecapeptide sequence strongly supports the notion that this portion of the polypeptide plays an important functional or structural role common to many P-450s.…”

Section: Discussionmentioning

confidence: 86%

Gene conversion in a cytochrome P-450 gene family.

Atchison¹,

Adesnik²

1986

Proc. Natl. Acad. Sci. U.S.A.

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The mRNAs encoding the two major phenobarbital-inducible forms of cytochrome P-450 of rat liver, P-450b and P-450e, are remarkably similar (98% homologous) in nucleotide sequence, but the distribution of differences within them is not random. While the 5' halves (s1 kilobase) appear to be identical, there are 36 divergent residues in the remaining sequences of the two mRNAs, with 14 differences residing in two short highly divergent segments, which in the P-450e gene are located within exon 7. DNA sequence analysis of portions of a number of P-450b/e-related genes provides strong evidence that at least one ofthe short divergent segments is the result of a recent gene conversion event between an ancestor to the cytochrome P-450e gene and a related donor P450 gene of unknown function. The sequence data also suggest that extensive gene conversion has occurred within all the members of this gene family in the region including exons 7 and 8 and the intron between them, with a resultant homogenization of those sequences relative to other portions of the genes. Genomic Southern blotting analysis demonstrates that the presence of an apparent "constant" region in the 5' halves of the P-450b and P-450e mRNAs does not reflect a rearrangement in somatic cells of a germ-line DNA configuration. It is therefore proposed that it, too, is a consequence of a very recent gene conversion event between ancestors of the genes encoding both proteins or of an unequal crossing-over between them. On the basis of these and other data we propose that gene conversion represents an important evolutionary mechanism for the generation of related cytochrome P-450 isozymes in which regions of extraordinary sequence similarity and dissimilarity are intermixed. The gene conversion mechanism would account for some of the overlaps in substrate specificities of distantly related P-450s as well as for substantial differences in catalytic properties between closely related members of the same P450 protein family.It has long been recognized (1) that members of a multigene family within a single species are generally much more closely related to each other than to equivalent (orthologous) genes in other species. This concerted evolution ofgenes that have had at least as long a time to diverge from each other as from their orthologous counterparts may result from unequal crossing-over between tandemly linked genes or from either double reciprocal recombination or gene conversion (1). The latter term refers to a nonreciprocal recombination event in which a segment of one gene replaces the corresponding segment of a related gene (2). The occurrence of homogenizing gene conversion events in the human a-globin (3), human fetal '-tglobin (4), oxytocin-vasopressin (5), and immunoglobulin (6) gene families has been inferred from a comparison of DNA sequences.t It has recently become apparent that gene conversion may also produce short regions of high diversity within closely related members of a multigene family, when the donor gene for the conversion is...

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Section: Discussionmentioning

confidence: 86%

Gene conversion in a cytochrome P-450 gene family.

Atchison¹,

Adesnik²

1986

Proc. Natl. Acad. Sci. U.S.A.

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“…The molecular weights of CYP1A1 (GenBank Accession No. NP034122) 23) and CYP1A2 (NP034123), 24) calculated from their mRNAs, are 59.229 and 58.183 KD, respectively. It is also known that CYP1A1 protein migrates slightly forward of CYP1A2 in SDS-PAGE (Professor N. Nemoto of Toyama Medical and Pharmaceutical University, personal communication).…”

Section: Resultsmentioning

confidence: 99%

Induction of Cytochrome P450 1A1 in Mice by Repeated Oral Administration of Propranolol

Narimatsu

Mochida

Ueno

et al. 2002

Drug Metabolism and Pharmacokinetics

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Pretreatment of adult male C57BL/6 mice with propranolol (PL, 100 mg/kg, p.o., once a day for five days) significantly increased PL N-deisopropylase activity and decreased PL 7-hydroxylase activity in liver microsomes, whereas PL 4- and 5-hydroxylase activities remained unchanged. In the present study, we have examined the mechanism for the elevation of the oxidation of PL side chain. Immunoblot analysis using polyclonal antibodies raised against rat liver CYP enzymes such as CYP1A1, -2B2, -2C11, -2D2, -2E1 and 3A2 showed that, compared with the vehicle-treated control, the levels of two protein bands (54 KD and 52 KD) were increased by the pretreatment. Both proteins immunochemically cross-reacted with the antibodies against rat CYP1A1, and from their molecular weights, the 54 KD and 52 KD proteins were deduced to be CYP1A1 and 1A2, respectively. Computer-assisted scanning analysis revealed that the levels of CYP1A1 and CYP1A2 proteins were increased 1.8 and 1.2 times, respectively, over those of control microsomes. PL N-deisopropylase activity correlated well with ethoxyresorufin O-deethylase (r=0.828) and phenacetin O-deethylase (r=0.851) activities in the same microsomal fractions. These results show that repeated oral administration of PL in mice induces mainly CYP1A1 and also CYP1A2 to some extent, which contrasts from our previous results in rats in which CYP1A2 only was induced with PL pretreatment [Narimatsu et al., Chemico-Biol. Interact., 101, 207-224 (1996)].

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“…The full-length mouse P3450 coding sequence, originally isolated using the pcD mammalian expression vector (29,30), was kindly provided by Daniel Nebert (University of Cincinnati Medical Center, Cincinnati) in a plasmid designated pmP3450FL (29). Digestion ofthis plasmid with BamHI released an insert of 2.0 kilobases and two other fragments that did not match pcD (31).…”

Section: Methodsmentioning

confidence: 99%

Introduction of cytochrome P450IA2 metabolic capability into cell lines genetically matched for DNA repair proficiency/deficiency.

Thompson

Felton

1991

Proc. Natl. Acad. Sci. U.S.A.

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We introduced into the CHO cell line the cDNA of the mouse cytochrome P3450 (P450IA2) gene, which oxidizes aromatic amines. A cDNA clone of P3450 was transfected into mutant UV5 cells, which is defective in nucleotide excision repair. Expression of the P3450 cDNA was measured using 9000 x g supernatant (S9) fractions from CHO cells to evaluate Salmonella TA1538 mutagenicity with the mutagen 2-amino-3-methylimidazo[4,5-fjquinoline (IQ). The P3450-expressing clone UV5P3 was reverted to repair proficiency using ethyl methanesulfonate to obtain the UV-resistant clone 5P3R2, which maintained the same level of P3450 protein activity as UV5P3. These genetically similar cell lines were compared for toxicity and mutation induction at the aprt locus.With 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (the most prevalent mutagen found in fried beef) the differential sensitivity due to repair deficiency/proficiency was -40-fold, and with IQ there were smaller, but sinfcant, differences in sensitivity. These genotoxic effects occurred at doses that were '10 times lower than those that previously gave similar effects in S9-mediated assays. Thus, these cell lines should be valuable for genotoxicity analysis as well as important for assessing DNA repair when evaluating compounds that undergo metabolic activation.

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Mouse cytochrome P₃-450: complete cDNA and amino acid sequence

Cited by 59 publications

References 41 publications

Gene conversion in a cytochrome P-450 gene family.

Gene conversion in a cytochrome P-450 gene family.

Induction of Cytochrome P450 1A1 in Mice by Repeated Oral Administration of Propranolol

Introduction of cytochrome P450IA2 metabolic capability into cell lines genetically matched for DNA repair proficiency/deficiency.

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Mouse cytochrome P3-450: complete cDNA and amino acid sequence

Cited by 59 publications

References 41 publications

Gene conversion in a cytochrome P-450 gene family.

Gene conversion in a cytochrome P-450 gene family.

Induction of Cytochrome P450 1A1 in Mice by Repeated Oral Administration of Propranolol

Introduction of cytochrome P450IA2 metabolic capability into cell lines genetically matched for DNA repair proficiency/deficiency.

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Mouse cytochrome P₃-450: complete cDNA and amino acid sequence