Lack of the Steroid 15α-Hydroxylase Gene (Cyp2a-4) in Wild Mouse Strain Mus spretus: Rapid Evolution of the P450 Gene Superfamily

Aida, Kaoru; Moore, Rickie; Negishi, Masahiko

doi:10.1006/geno.1994.1107

Cited by 11 publications

(7 citation statements)

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“…This hypothesis is supported by the fact that the 2a5 and 2g1 genes on the telomeric side of the cluster are transcribed in the same direction and are spaced a similar distance apart as are the 2a4 and 2g1-ps loci on the centromeric side. It is also consistent with the suggestion of Aida et al (1994) that because Mus musculus has both 2a4 and 2a5 genes, whereas its close relative Mus spretus appears to have two nearly identical 2a5-like loci, 2a4 must have been formed recently by the alteration of a critical residue in a previously duplicated copy of the 2a5 gene.…”

Section: Discussionsupporting

confidence: 90%

Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Wang

Donley

Keeney

et al. 2003

Environ Health Perspect

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Genes from the cytochrome P450 (CYP) superfamily encode a diverse group of monooxygenases that play important roles in both endogenous processes and in the metabolism of exogenous compounds, including most drugs. A cluster of Cyp2 genes on mouse chromosome 7 was mapped and analyzed in detail and compared with the homologous cluster on human chromosome 19. The mouse cluster includes 22 loci from the same six CYP2 subfamilies-Cyp2a, Cyp2b, Cyp2f, Cyp2g, Cyp2s, Cyp2t-that are found in the human cluster. Twelve of these loci are functional genes, and 10 are pseudogenes. Parts of the mouse and human gene clusters are similarly arranged, but the data indicate that a significantly different series of duplication events created the modern gene organizations in the two species. The comparison of the mouse and human clusters provides new insights into the evolution of gene families, whereas the detailed analysis provides background information that should be informative for future studies on the expression, regulation, and function of specific mouse Cyp2 genes.

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Section: Discussionsupporting

confidence: 90%

Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Wang

Donley

Keeney

et al. 2003

Environ Health Perspect

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“…Cyp2a-4 especially appears to be sensitive to mutations, as it shows a microdiversity in its amino acid sequence. For example, the wild mouse Mus spretus appears to lack the Cyp2a-4 gene [31]. Furthermore, the Cyp2a-4 from 129/J mice differs by four amino acids from its counterpart from DBN2J mice, which may affect the testosterone-1 5a-hydroxylase activity [39].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of a cytochrome P‐450 of the 2a family (Cyp2a‐5) in chemically induced hepatomas from female mice

Jounaïdi

Bonfils

Périn

et al. 1994

European Journal of Biochemistry

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Chemical hepatocarcinogenesis in female mice, induced by 5,9-dimethyl(7H)dibenzo[c,g]carbazole, leads to the overexpression of a cytochrome P-450 of the 2a family. This protein was identified as Cyp2a-5, by the use of immunoblots obtained from isoelectric focusing gels. This method allowed the distinction of Cyp2a-5 from Cyp2 a-4, another mouse liver cytochrome P-450, by taking advantage of their slightly different PI values. The theoretical PI values, determined from the amino acid sequence, were PI 9.91 for Cyp2a-4 and PI 10.01 for Cyp2a-5. Other structurally related forms were not detected. In hepatomas from female mice, only the Cyp2a-5 form was overexpressed (2-3 fold). Male mice showed a weak expression of Cyp2a-4 and Cyp2a-5 in control liver samples and in hepatomas. The expression of both forms was increased more than fivefold upon castration. Pyrazole induces specifically the Cyp2 a-5 form. The Cyp2 a-5 overexpression was correlated with enhanced microsomal coumarin-7-hydroxylase and testosterone-1 5a-hydroxylase activities.An immunohistochemical study showed that Cyp2a-4and Cyp2a-5 are expressed uniformly in female livers, but centrilobularly in male livers. In hepatomas, this localisation is perturbed; in females we observed a focal cell localisation, and the Cyp2a-containing cells were often hypertrophic and polyploid. In hepatomas from male mice, the Cyp2a-containing cells became dispersed.From a comparison with other studies, the Cyp2a-5 overexpression appears to be a general feature of hepatocarcinogenesis in mice.Some years ago, we started the biochemical characterisation of mouse liver tumours via the analysis of their cytochrome P-450 content. Our study was facilitated by the use of 5,9-dimethyl(7H)dibenzo[c,g]carbazole. This compound was revealed to be an organ-specific tumour-inducing agent ; subcutaneous injection into female 17nc/Z mice provokes hepatomas in almost 100% of treated animals [l]. In rats, a differential cytochrome P-450 expression during hepatocarcinogenesis has also been reported [2]. We chose the cytochrome P-450 2a family, beause the expression of its forms is regulated differentially, depending on tissue type, hormonal status and drug administration [3, 41. Hepatomas are characterised by an altered expression of several proteins [5-71, among criterion, we recently isolated a particular microsomal P-450 form (cytochrome P-450,) from hepatomas of female 17nc/ Z mice [11]. This cytochrome P-450 appeared to belong to the Cyp2a family, it had the same N-terminal amino acid sequence as Cyp2a-4 and Cyp2a-5, which are two sex-dependent mouse liver microsomal cytochrome P-450 forms, specific for testosterone hydroxylation at the 15a position and coumarin hydroxylation at the 7 position, respectively [ 121. Furthermore, antibodies raised against cytochrome P-450, cross-reacted with a human liver microsomal P-450 form, and were used to isolate the orthologous CYP 2 A6[ 131. It was therefore important to define better the structural relationship of this protein, which is overexpre...

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“…Five Cyp 2A cDNAs were cloned from the wild mouse strains Mus minutoides (mP450 2a-5), and Mus spretus (sP450 2a-5) and the domestic mouse strains Mus musculus domesticus (dP450 2a-51, dP450 2a5H, and dP45O 2a-4). P450 2a-4 appears to be present only in domestic mice (10). These P450s were expressed either in bacterial or yeast cells and were then purified for further characterization.…”

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confidence: 99%

Structural flexibility and functional versatility of mammalian P450 enzymes

et al. 1996

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P450 enzymes have evolved into a large superfamily that displays great diversity in substrate and product specificities by fixing the natural amino acid substitutions with high frequency. Site-directed mutagenesis has been used to correlate the substitutions with the diverse specificities in various P450s. As a result, the common residues that determine the specificities of various mammalian P450s have been identified and aligned to the corresponding residues in the substrate-heme pocket of the 3-dimensional structures of bacterial P450s. The substrate-heme pocket appears to be structurally variable so that only a minor substitution (Ala -> -> Val, for example) at the critical positions is enough to define the altered specificity. Thus, the structural variability of the P450s provides the inherent versatility in acquiring a novel activity. Recent mutational studies indicate that the side chain size is the major determining factor of specificity, outweighing other factors such as polarity. Further understanding of the paradoxical characteristics observed may provide us with the underlying principles that determine P450 activities, and may lead to the ability to predict P450 activities based on the types of key amino acid residues.

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Lack of the Steroid 15α-Hydroxylase Gene (Cyp2a-4) in Wild Mouse Strain Mus spretus: Rapid Evolution of the P450 Gene Superfamily

Cited by 11 publications

References 0 publications

Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Overexpression of a cytochrome P‐450 of the 2a family (Cyp2a‐5) in chemically induced hepatomas from female mice

Structural flexibility and functional versatility of mammalian P450 enzymes

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