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PubMed1998

NHE-1 is the sodium-hydrogen exchanger isoform present in erythroid cells.

Erythrocyte sodium hydrogen exchanger (NHE) represents one of a limited number of sodium entry pathway in erythrocytes. At least five NHE isoforms have been identified, differing in tissue specificity, regulatory characteristics, and pharmacological sensitivities. Although physiological characteristics of erythrocyte NHE suggest that the widely expressed NHE-1 isoform may be present, evidence is not conclusive and does not exclude the existence of other isoforms. In this study, Northern blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses were used to test for five NHE isoforms in erythroid cells. Blood from patients with sickle cell disease was depleted of white blood cells (WBC) by passage through leukocyte filters and cellulose column. RT-PCR performed on WBC depleted reticulocyte RNA using a NHE-1 primer set yielded product a of expected size, the sequence of which was identical to the published human NHE-1 sequence. Northern blot analysis of the reticulocyte RNA using a 1.6 kb probe revealed a message of approximately 5.0 kb in size. RT-PCR analysis of rat kidney RNA using primers specific for NHE isoforms -2, -3, -4 and rat brain RNA using primer specific for NHE-5 isoform yielded products of expected size, whereas WBC depleted RNA under identical conditions yielded no products. These results identify the erythroid isoform of the sodium hydrogen exchanger as NHE-1.

Animals↗
PubMed2000

Down-regulation of Na(+)/K(+)-ATPase alpha(2) isoform in denervated rat vas deferens.

In the rat vas deferens, an organ richly innervated by peripheral sympathetic neurons, we have demonstrated recently the expression of alpha(1) and alpha(2), but not alpha(3) isoforms of the alpha subunit of Na(+)/K(+)-ATPase (EC 3.6.1.37), a membrane-bound enzyme of vital function for living cells (Noël et al., Biochem Pharmacol 55: 1531-1535, 1998). In the present work, we characterized, qualitatively and quantitatively, Na(+)/K(+)-ATPase alpha isoforms in denervated rat vasa deferentia. [(3)H]Ouabain binding at concentrations defined for high-affinity isoforms (alpha(2) and/or alpha(3)) detected only one class of specific binding sites in control (C) and denervated (D) vas deferens. Although the dissociation constant was similar for both groups [K(d) = 138 +/- 14 nM (C) and 125 +/- 8 nM (D)], a marked decrease in density was observed after denervation [716 +/- 81 fmol.mg protein(-1) (C) and 445 +/- 34 fmol.mg protein(-1) (D), P < 0.05]. In addition, western blotting revealed that denervated vasa deferentia produce the alpha(1) and alpha(2) isoforms but not alpha(3), just as we reported for the controls previously (Noël et al., Biochem Pharmacol 55: 1531-1535, 1998). Densitometric analysis showed a decrease of the alpha(2) isoform by about 40% in denervated organs, in very good agreement with what was shown with the [(3)H]ouabain binding technique, but no significant change in alpha(1) isoform density. Truncated alpha(1) (alpha(1)T), an isoform suggested to exist in the guinea pig vas deferens, was not detected. Altogether, our results demonstrated that Na(+)/K(+)-ATPase alpha(2) is down-regulated after sympathetic denervation of the rat vas deferens.

Animals↗
PubMed1991

Nonmammalian vertebrate skeletal muscles express two triad junctional foot protein isoforms.

Mammalian skeletal muscles express a single triad junctional foot protein, whereas avian muscles have two isoforms of this protein. We investigated whether either case is representative of muscles from other vertebrate classes. We identified two foot proteins in bullfrog and toadfish muscles on the basis of (a) copurification with [3H]epiryanodine binding; (b) similarity to avian muscle foot proteins in native and subunit molecular weights; (c) recognition by anti-foot protein antibodies. The bullfrog and toadfish proteins exist as homooligomers. The subunits of the bullfrog muscle foot protein isoforms are shown to be unique by peptide mapping. In addition, immunocytochemical localization established that the bullfrog muscle isoforms coexist in the same muscle cells. The isoforms in either bullfrog and chicken muscles have comparable [3H]epiryanodine binding capacities, whereas in toadfish muscle the isoforms differ in their levels of ligand binding. Additionally, chicken thigh and breast muscles differ in the relative amounts of the two isoforms they contain, the amounts being similar in breast muscle and markedly different in thigh muscle. In conclusion, in contrast to mammalian skeletal muscle, two foot protein isoforms are present in amphibian, avian, and piscine skeletal muscles. This may represent a general difference in the architecture and/or a functional specialization of the triad junction in mammalian and nonmammalian vertebrate muscles.

Animals↗
PubMed2002

Na+, K+ ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle/myenteric plexus after exposure to morphine.

Previous work in the myenteric plexus has shown that the resting membrane potential of morphine-tolerant guinea-pig myenteric S neurons is significantly depolarized relative to placebo-implanted controls, and that this depolarization is associated with reduced electrogenic Na+, K+ pumping. Identification of the subunits of the sodium pump which are in the myenteric plexus was undertaken in order to facilitate direct qualitative and quantitative measurements of the abundance of sodium pump isoforms after morphine exposure, thereby confirming and extending the electrophysiological data to the molecular level. Seven days prior to the experiments, tolerance was induced by subcutaneous implantation of morphine pellets (one pellet, 75 mg/100 g body weight) while control guinea pigs received placebo pellets. Using immunohistochemistry and confocal microscopy, the distribution of the alpha subunit isoforms of the Na+/K+ -ATPase in placebo and morphine-tolerant guinea-pig ileum was determined. Only the alpha1 and alpha3 subunit isoforms were in sufficient abundance to be observed. The alpha1 subunit isoform was most highly concentrated in the mucosa and in neurons. In contrast, the alpha3 subunit isoform was uniquely localized to neurons. Western and slot blot analyses of longitudinal muscle/myenteric plexus homogenates identified a significant reduction of the alpha3 but not the alpha1 subunit isoform in tolerant preparations. It is concluded that the reduced electrogenic pumping in the S neurons after morphine exposure is associated with a reduction in the alpha3 subunit isoform.

Animals↗
PubMed1999

Non-uniform expression of alpha subunit isoforms of the Na+/K+ pump in rat dorsal root ganglia neurons.

Tissue sections and antibodies selectively recognizing isoforms of the alpha subunit of the Na+/K+ pump were used to determine the expression of alpha1, alpha2 and alpha3 pump isoforms in the plasma membrane of adult rat dorsal root ganglia (DRG) neurons. There was no detectable membrane signal from DRG neurons that were probed with antibodies to the alpha2 isoform of the Na+/K+ pump. The alpha1 isoform of the Na+/K+ pump was found in most (77+/-4%) studied DRG neurons, regardless of cell size. Only 16+/-7% of the neurons expressed a detectable level of the alpha3 Na+/K+ pump and all were apparently from a subpopulation of large DRG neurons. Comparison of cell size distributions and a study of neurons identified in serial sections suggested that of the alpha3 positive DRG neurons about 75% coexpressed the alpha1 isoform of the Na+/K+ pump. These data show that the expression of the protein of the alpha subunit isoforms of the Na+/K+ pump is not uniform throughout the population of DRG neurons and that alpha1 is the predominant isoform in the plasma membrane of these neurons.

Animals↗
PubMed2000

CK-MB isoforms for early risk stratification of emergency department patients.

The potential clinical utility of single sample CK-MB isoforms measurement for early risk stratification of Emergency Department (ED) patients with possible myocardial ischemia was evaluated among 405 patients presenting to two urban EDs. Clinical and serologic data were prospectively collected and the occurrence of adverse events (AEs) and myocardial infarction (MI) during the 14-day outcome period was recorded and utilized to calculate and compare relative risks (RR) and predictive values of isoforms and CK-MB alone. Among the 405 patients, 67 accrued 105 AEs. Both isoforms and CK-MB alone were predictive of AEs with RR of 3.32 (2.09, 5.27) and 6.28 (4.64, 8.52), respectively. Isoforms had higher sensitivity for AEs compared to CK-MB (65.7% [54.3, 77.0] vs. 14.9% [6.4, 23.5]; p<0. 01) but lower specificity (69.2% [64.3, 74.2] vs. 99.7% [99.1,100. 0]; p<0.01). Isoforms' superior sensitivity allowed identification of many high risk patients missed by CK-MB alone. Further, for the prediction of MI, isoforms had superior diagnostic sensitivity and equivalent specificity. This investigation supports the emergency department use of early, single sample CK-MB isoform testing.

Adult↗
PubMed1998

Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes.

Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperphosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.

Alzheimer Disease↗
PubMed2002

Thyroidal regulation of different isoforms of NaKATPase in the primary cultures of neurons derived from fetal rat brain.

The developmental profile of the different isoforms of NaKATPase have been investigated using primary cultures of isolated neurons initiated from 17 day old fetal rat brain. Northern blot analysis showed that the expression of three alpha isoforms (alpha(1), alpha(2) and alpha(3)) and two beta isoforms (beta(1) and beta(2)) increased progressively and reached a peak between 12 to 16 days of culture. Comparison of the mRNA levels of these isoforms in the cells maintained in thyroid hormone deficient (TH def) and thyroid hormone supplemented (TH sup) media for 6-12 days, revealed for the first time that in the neurons three alpha and two beta isoforms of NaKATPase are sensitive to TH. Furthermore immunocytochemical staining of these cells with isoform specific NaKATPase antibodies showed that the uniform distribution of alpha(2), alpha(3) and beta(2) isoforms in the neuronal processes require the presence of TH. These results establish neurons as the target cells for the regulation of NaKATPase by TH in the developing brain.

Animals↗
PubMed1998

Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals.

All three major isoforms of nitric oxide synthase (NOS) are expressed in the brain. Because of complex and overlapping expression patterns (Marletta, 1994; Nathan and Xie, 1994), the particular NOS isoform involved in many processes is not clear. In fact, NO generated by separate isoforms may have different roles and potentially opposing effects (Iadecola et al., 1994). We have taken a genetic approach, to disrupt or knockout the genes for NOS isoforms to circumvent some of the limitations of pharmacologic agents. This approach allows the study of each individual NOS isoform in physiologic processes in the context of intact animals. It gives insights into possible developmental roles for NO and parallel processes that may compensate for the absence of each NOS isoform. We have made nNOS and eNOS knockout mice, as well as double knockout mice that lack both nNOS and eNOS isoforms (Huang et al., 1993; Huang et al., 1995; Son et al., 1996). In this chapter, we review some of the physiologic roles for NO that have been elucidated making use of these mice, including regulation of cerebral blood flow, response to cerebral ischemia, regulation of neurotransmitter release in the brain, and development of synaptic plasticity. Other chapters will discuss results using NOS knockout animals in studies of long term potentiation (see Hawkins, this volume), neuronal development (see Mize, this volume), and potential mechanisms for protection in nNOS knockout mice (Moskowitz, M.A.; Dawson, V.L, this volume).

Animals↗
PubMed1996

Differential expression of protein kinase C isoforms in the human placenta.

The extensive role played by protein kinase C (PKC) in signal transduction prompted this study of the expression and localization of PKC isoforms in human placental syncytiotrophoblast. Membranes prepared from these cells and samples of villous tissue were analysed by immunoblotting and immunocytochemistry using isoform-specific antibodies. PKC beta 2, gamma, epsilon and zeta were found to be present in both microvillous and basal membranes from term placenta. The alpha isoform was observed only on the basal membrane while the beta 1 isoform was confined to the microvillous membrane. The basal microvillous ratios for beta 2, gamma, epsilon and zeta ranged between 0.3 and 0.5, demonstrating a substantial asymmetry in plasma membrane localization. Immunocytochemistry supported the isoform identification and localization observed in the immunoblotting experiments. Moreover the cellular distribution showed that the majority of syncytical PKC was bound to the plasma membranes, in contrast to the other villous cell types. Immunoblotting experiments demonstrated significant increases in PKC beta 2 and epsilon on the microvillous membrane and PKC gamma and epsilon on the basal membrane between 16 and 40 of weeks gestation. This is the first detailed mapping of PKC isoform distribution in an epithelial cell type and demonstrates the potential for selectivity in signal transduction through phosphorylation of isoform specific and spatially-separated substrates.

Amino Acid Sequence↗
PubMed1997

The isolation of parvalbumin isoforms from the tail muscle of the American alligator (Alligator mississipiensis).

Multiple parvalbumin isoforms have been detected in the tail (skeletal) muscle of the American alligator (Alligator mississipiensis). One of these isoforms (APV-1) has been highly purified and partially characterized. Protein purification involved mainly gel filtration and anion exchange chromatography, and characterization included gel electrophoresis, amino acid composition analysis, metal ion analysis, MALDI-TOF and ESI mass spectrometry, ultraviolet and fluorescence spectroscopy, and one- and two-dimensional 500 MHz proton NMR spectroscopy. The alligator isoforms are rich in phenylalanine and deficient in the other aromatic residues as is typical for parvalbumins. In fact, the one highly purified isoform that forms the basis of this study has only phenyl-alanine as an aromatic residue. Ion exchange chromatography further indicates that this isoform has a relatively high isoelectric point (pl approximately 5.0), indicating that it is an alpha-lineage parvalbumin. This alligator parvalbumin isoform is unusual in that it has an atypically high Ca2+ content (almost 3.0 mole of Ca2+ per mole of protein) following purification, a fact supported by terbium fluorescence titration experiments. Preliminary comparative analysis of the highly purified alligator parvalbumin isoform (in the Ca2-loaded state) by two-dimensional 1H-NMR (2D 1H TOCSY and 2D 1H NOESY) indicates that there is considerable similarity in structure between the alligator protein and a homologous protein obtained from the silver hake (a saltwater fish species).

Alligators and Crocodiles↗
PubMed1999

Isoforms of the small non-catalytic subunit of smooth muscle myosin light chain phosphatase.

Chicken gizzard smooth muscle myosin light chain phosphatase is composed of a approximately 37 kDa catalytic subunit, a approximately 110 kDa myosin binding or targeting subunit and a approximately 20 kDa subunit (MPs) whose function is as yet undefined. It was reported previously that a cloned chicken gizzard MPs cDNA encodes a protein of 186 amino acids (aa) [Y.H. Chen, M.X. Chen, D.R. Alessi, D.G. Gampbell, C. Shanahan, P. Cohen, P.T.W. Cohen, FEBS Lett. 356 (1994) 51-55]. More recently, we obtained by PCR amplification another MPs cDNA that encodes a protein of only 161 aa [Y. Zhang, K. Mabuchi, T. Tao, Biochim. Biophys. Acta 1343 (1997) 51-58]. In this work we obtained cDNAs corresponding to both sequences using a different set of PCR primers, indicating that the two sequences correspond to isoforms that most likely arose from alternative splicing of the same gene. Using two polyclonal antibodies, one raised against the recombinant 161 aa isoform of chicken gizzard MPs and the other against a C-terminal polypeptide that is present only in the 186 aa isoform, we found that while the 161 aa isoform is the predominant one in chicken gizzard, in chicken aorta it is the 186 aa one; in chicken stomach both isoforms are present, and in mammalian tissues such as ferret and rat only the 186 aa isoform is detected. Furthermore, we purified the MPs associated with the chicken gizzard myosin light chain phosphatase holoenzyme and determined its molecular weight, amino acid composition and six residues of its C-terminal sequence. The results from these analyses showed conclusively that the predominant isoform in chicken gizzard is the 161 aa one.

Amino Acid Sequence↗
PubMed1998

Identification and expression of two novel CLIP-170/Restin isoforms expressed predominantly in muscle.

CLIP-170 and Restin, microtubule-binding proteins originally cloned from human cells, are identical except for a stretch of 35 amino acids present in Restin, but missing from CLIP-170. Here we present the discovery of two novel isoforms of the CLIP-170/Restin gene in both chickens and humans. One of the new isoforms, named CLIP-170(11), contains an 11 amino acid insert instead of the 35 amino acid insert found in Restin. Eight of these 11 amino acids, including a helix-breaking proline residue, are perfectly conserved between chickens and humans. The second new isoform, named CLIP-170(11+35), contains both the 11 and 35 amino acid inserts in tandem. PCR analysis of chicken genomic DNA revealed that all four isoforms result from differential splicing of two exons in a region of the CLIP-170 gene that contains approximately 8.6 kb of intervening sequence. We found that the CLIP-170(11) and CLIP-170(11+35) are expressed preferentially in muscle tissues. Chicken and human skeletal muscle express predominantly CLIP-170(11) and to a lesser extent CLIP-170 and CLIP-170(11+35). Adult chicken cardiac and smooth muscles also express CLIP-170(11) and CLIP-170(11+35), but CLIP-170 is the predominant isoform in these muscles as it is in all other tissues except brain. The ratios of CLIP-170 isoform expression found in embryonic and adult chicken cardiac muscles reveal that isoform expression is regulated differentially in different developmental stages as well as in different tissues.

Alternative Splicing↗
PubMed1998

A new concept in laryngeal muscle: multiple myosin isoform types in single muscle fibers of the lateral cricoarytenoid.

This report describes the first known investigation of canine laryngeal muscle in which single fibers were dissected and their myosin heavy chain (MHC) isoform content was analyzed. Both SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot techniques were used. The data from single fiber SDS-PAGE indicate that the lateral cricoarytenoid (LCA) is predominantly a fast muscle composed of the following MHC isoforms: Type I, 16.3%; Type IIA, 71.3%; Type IIX, 10.4%; and Type IIB, 2.0%. The results reveal a phenomenon that, to our knowledge, has not been previously described for laryngeal muscle: the presence of two or more MHC isoforms in a single canine LCA muscle fiber. A large number (41%) of muscle fibers coexpressed two or more MHC isoforms. The three most common patterns of coexpression were Type IIA/IIX (72%), Type IIA/I (16%), and Type IIA/IIX/I (8%). Interestingly, the fast Type IIX MHC isoform was typically present with other isoforms and rarely found by itself in individual fibers. Additional experiments are underway to determine whether other laryngeal muscles exhibit such an unusually high ratio of MHC isoform polymorphism.

Animals↗
PubMed2003

Lipid binding ability of human apolipoprotein E N-terminal domain isoforms: correlation with protein stability?

Human apolipoprotein (apo) E exists as one of three major isoforms, E2, E3 or E4. Individuals carrying the epsilon 4 allele have an increased risk of heart disease and premature onset of Alzheimer's disease. To investigate the molecular basis for this phenomenon, the N-terminal domain of apoE3, apoE2 and apoE4 were expressed in bacteria, isolated and employed in lipid binding and stability studies. Far UV circular dichroism spectroscopy in buffer at pH 7 revealed a similar amount of alpha-helix secondary structure for the three isoforms. By contrast, differences were noted in apoE-NT isoform-specific transformation of bilayer vesicles of dimyristoylphosphatidylglycerol (DMPG) into discoidal complexes. ApoE4-NT induced transformation was most rapid, followed by apoE3-NT and apoE2-NT. To determine if differences in the rate of apoE-NT induced DMPG vesicle transformation is due to isoform-specific differences in helix bundle stability, guanidine HCl denaturation studies were conducted. The results revealed that apoE2-NT was the most stable, followed by apoE3-NT and apoE4-NT, establishing an inverse correlation between helix bundle stability and DMPG vesicle transformation rate at pH 7. When the zwitterionic dimyristoylphosphatidylcholine (DMPC) was employed as the model lipid surface, interaction of apoE-NT isoforms with the lipid substrate was slow. However, upon lowering the pH from 7 to 3, a dramatic increase in the rate of DMPC vesicle transformation rate was observed for each isoform. To evaluate if the increased DMPC vesicle transformation rates observed at low pH is due to pH-dependent alterations in helix bundle stability, guanidine HCl denaturation studies were performed. ApoE2-NT and apoE3-NT displayed increased resistance to denaturation as a function of decreasing pH, while apoE4-NT showed no change in stability. Studies with the fluorescent probe, 8-anilino-1-naphthalene sulfonic acid, indicated an increase in apoE hydrophobic surface exposure upon decreasing the pH to 3.0. Taken together, the data indicate that changes in the stability of secondary structure elements in apoE-NT isoforms are not responsible for pH-induced increases in lipid binding activity. It is likely that pH-induced disruption of inter-helical tertiary contacts may promote helix bundle conformational changes that present the hydrophobic interior of the protein to potential lipid surface binding sites.

Apolipoproteins E↗
PubMed2001

Possible involvement of PKC isoforms in signalling placental apoptosis in intrauterine growth retardation.

Apoptosis contributes to uteroplacental dsyfunction in intrauterine growth retardation (IUGR). Specific protein kinase C (PKC) isoforms regulate apoptosis in other cell types. PKC isoforms thought to be anti-apoptotic include the conventional PKC isoforms (cPKC-alpha, -beta I and -beta II), whereas the novel PKC isoforms nPKC-delta and nPKC-epsilon may be apoptotic. Dexamethasone administration during the last third of pregnancy in the rat leads to IUGR. We used the dexamethasone model to test the hypothesis that adverse changes in fetal growth might be associated with a modified placental PKC isoform profile. Dexamethasone administered from day 15 of gestation via subcutaneous infusion (osmotic minipump; 100 or 200 microg dexamethasone/kg maternal body wt. per day) induced a dose-dependent decline in placental and fetal body weights at day 21 of gestation. Placental protein expression of all three cPKC isoforms was downregulated by maternal dexamethasone exposure, whereas placental nPKC-epsilon protein expression and activity was significantly upregulated in a dose-dependent manner. These data indicate that IUGR induced by excessive glucocorticoid exposure late in pregnancy leads to changes in the placental PKC isoform profile consistent with the concept that members of the PKC family participate in apoptosis signalling in the placenta.

Animals↗
PubMed1998

Six isoforms of cardiotoxin in malayan spitting cobra (Naja naja sputatrix) venom: cloning and characterization of cDNAs.

Cardiotoxins are the most abundant toxin components of cobra venom. Although many cardiotoxins have been purified and characterized by amino acid sequencing and other pharmacological and biochemical studies, to date only five cardiotoxin cDNAs from Taiwan cobra (Naja naja atra), three cDNAs from Chinese cobra (Naja atra) and two more of uncertain origin (either Chinese or Taiwan cobra) have been reported. In this paper we show the existence of four isoforms of cardiotoxin by protein analysis and nine cDNA sequences encoding six isoforms of cardiotoxins (CTX 1-3, 4a, 4b and 5) from N. n. sputatrix by cDNA cloning. This forms the first report on the cloning and characterization of several cardiotoxin genes from a single species of a spitting cobra. The cDNAs encoding these isoforms, obtained by reverse transcription-polymerase chain reaction (RT-PCR), were subsequently expressed in Escherichia coli. The native and recombinant cardiotoxins were first characterized by Western blotting and N-terminal protein sequencing. These proteins were also found to have different levels of cytolytic activity on cultured baby hamster kidney cells. Four of the isoforms (CTX 1, 2, 4 and 5) are unique to N. n. sputatrix, with CTX 2 being the most abundant species constituting about 50% of the total cardiotoxins. The isoform CTX 3 (20% constitution) is highly homologous to the cardiotoxins of N. n. atra and N. n. naja, indicating that it may be universally present in all Naja naja subspecies. Our studies suggest that the most hydrophilic isoform (CTX 5) could have evolved first followed by the hydrophobic isoforms (CTX 1, 2, 3 and 4). We also speculate that Asiatic cobras could be the modern descendants of the African and Egyptian counterparts.

Amino Acid Sequence↗
PubMed2003

Predominantly neuronal expression of cytochrome P450 isoforms CYP3A11 and CYP3A13 in mouse brain.

Despite the very small amounts of cytochrome P450 enzymes expressed in different areas and cell populations of the brain as compared with the liver, there is significant evidence for their specific involvement in brain development, function, and plasticity. Nevertheless, the current discussion about occurrence and importance of cerebral cytochrome P450 isoforms is determined by controversial interpretations of their function in general and with respect to single isoforms. Continuing a series of publications about brain P450 isoforms, we now present evidence for the expression of cytochrome P450 3A11 and 3A13 in mouse brain. Immunocytochemical and non-radioactive in situ hybridization studies revealed identical distribution of their proteins and mRNAs throughout the brain especially in neuronal populations, and to some extent in astrocytes. The cerebral expression of these P450 isoforms was confirmed by Western blot and RNAse protection assay analysis. The well-known testosterone-metabolizing capacity and the inducibility of cytochrome P450 3a isoforms by xenobiotics as well as their presence in steroid hormone-sensitive areas and neurons (e.g. hippocampus) clarify the significance of these isoforms for impairment of steroid hormone actions by P450-inducing environmental substances. Therefore, investigation of inducible cerebral P450 isoforms which are able to metabolize xenobiotics as well as steroid hormones might help us to understand neuroendocrine regulation of brain's plasticity.

Animals↗