Heterogeneous expression of phenobarbital-inducible cytochrome P-450 genes within the hepatic acinus in the rat

Chianale, José; Dvorak, Caroline; May, Maryann; Gumucio, Jorge J.

doi:10.1002/hep.1840060522

Cited by 20 publications

(14 citation statements)

References 25 publications

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“…To begin to understand the factors that might contribute to the liver developmental program, a number of laboratories have begun to use molecular probes to study the patterns of expression of specific genes under various circumstances, e.g., during normal development (SalaTrepat et al 1979;Liao et al 1980;Tilghman and Belayew 1982;Meeham et al 1984;Powell et al 1984;Sellem et al 1984;Giachielli and Omiecinski 1986;Poliard et al 1986), during liver regeneraton Tamaoki and Fausto 1984;Panduro et al 1986), in different regions of the hepatic lobule (Chianale et al 1986), in isolated hepatocytes (Clayton and Darnell 1983;Jefferson et al 1984;Jefferson et al 1985), and in various hepatoma cell lines, variants, and somatic cell hybrids (Peterson and Weiss 1972;Darlington et al 1974;Peterson 1976;Clayton et al 1985b). Most of these studies have been limited to analysis of steady-state levels of one or a few related mRNAs under a variety of circumstances.…”

Section: Discussionmentioning

confidence: 99%

Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Panduro¹,

Shalaby²,

Shafritz³

1987

Genes Dev.

100

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Genes coding for unique or tissue-specific (differentiated) functions in the liver are induced at different times during development. It has generally been felt that transcriptional control represents the dominant mechanism for regulating expression of these genes. We have determined the relative transcription rates and mRNA steady-state levels for a series of genes specifically or preferentially expressed in rat liver and find examples of transcriptional control (albumin, a-fetoprotein, a~-antitrypsin, tyrosine aminotransferase, transferrin, and cytochrome P450, TF-1) and post-transcriptional control (a~-acid glycoprotein, apolipoproteins A-1 and E, malic enzyme, and ATP citrate lyase), as well as "mixed" regulation (ligandin and cytochrome P450, RI7). Examples have been identified in which the predominant mode for regulating expression of preferentially expressed genes changes from transcriptional to post-transcriptional at different stages of liver development and some members of multigene families (cytochrome P450s and apolipoprotein genes) also show independent and sometimes contrasting modes of regulation. Therefore, it appears that regulation of specific gene expression in the liver is a dynamic process, far more complex than heretofore suspected, and a much greater contribution of posttranscriptional regulation accounts for changes in expression of genes representing major functions of the liver.

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Section: Discussionmentioning

confidence: 99%

Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Panduro¹,

Shalaby²,

Shafritz³

1987

Genes Dev.

100

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“…15 M NaCl. Previous studies in this laboratory have shown that the maximal induction of total cytochrome P-450 activity, assessed spectrophotometrically, is achieved by -33 h after a single dose of PB (9). Therefore, 33 h after a single dose of PB, snap-frozen pieces of liver were sectioned at 6 um in a cryostat.…”

Section: Hybridization Conditionsmentioning

confidence: 99%

“…shown (5,9). To assess whether pOHPB would induce these P-450 genes if administered in various doses, this drug was given as three daily doses of400 mg/kg, i.p.…”

Section: Quantitative Assessmentmentioning

confidence: 99%

“…However, in those preparations, it was difficult to quantitate the degree of contamination with hepatocytes of another zone. Specifically, in those studies (9), the exact localization in tissue of the hepatocytes that contained either the highest or the lowest levels of P-450b,e mRNA could not be defined. To this extent, the molecular mechanisms responsible for the heterogeneous expression of these genes in response to PB remained unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Studies using hepatocytes isolated predominantly from the proximal or distal half of the liver acinus suggested that the levels of cytochromes P-450b,e mRNA after administration of PB to rats, increased predominantly in hepatocyte subpopulations isolated from the distal half ofthe acinus (9). However, in those preparations, it was difficult to quantitate the degree of contamination with hepatocytes of another zone.…”

Section: Introductionmentioning

confidence: 99%

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Demonstration by in situ hybridization of the zonal modulation of rat liver cytochrome P-450b and P-450e gene expression after phenobarbital.

Wojcik¹,

Dvorak²,

Chianale³

et al. 1988

J. Clin. Invest.

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The various physiological processes that constitute liver function are compartmentalized within the hepatic acinus. The molecular mechanisms modulating the development and maintenance of this hepatocyte heterogeneity have not been defined. The objective of this study was to determine whether transcriptional or posttranscriptional zonal modulation of cytochromes P450b,e gene expression was responsible for the heterogeneous induction of the P450 proteins, which is observed after phenobarbital (PB) administration. The exact localization in liver tissue of hepatocytes responding to PB with induction of either P450b,e mRNA or proteins was established by in situ hybridization and by immunofluorescence, respectively. As demonstrated by quantitative assessment of autoradiographs of -20 hepatocytes located between a terminal portal venule and a hepatic venule, PB induced the P450b,e mRNA up to sixfold in the 12-15 hepatocytes located closer to the hepatic venules (zones 2 and 3). In contrast, there was only a twofold induction in the 4-6 hepatocytes surrounding the terminal portal venules (zone 1). Quantitative immunofluorescence using an MAb showed that the acinar distribution of PB-induced P450b,e proteins was similar to that of the mRNA. This combined approach indicated that, most likely, an increased rate of transcription of cytochromes P450b,e genes in hepatocytes of zones 2 and 3 concomitantly, with a relative lack of activation, or repression, of these genes in hepatocytes of zone 1, were responsible for the heterogeneous phenotype observed after PB administration. Therefore, modulation of gene expression among hepatocytes of the liver acinus is one mechanism by which the functional heterogeneity of hepatocytes is attained. Experiments in which the induction of cytochromes P450b,e genes was studied after administration of either PB or para-hydroxyphenobarbital, a main hepatic metabolite of PB, suggested that the species involved in the inductive process is the parent PB molecule rather than para-hydroxyphenobarbital.

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Cytochrome p-450 gene expression in the functional units of the fetal liver

et al. 1988

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Hepatocytes of the right and left lobes of the fetal liver are surrounded by different microenvironments. The right and left lobes of the fetal liver are perfused by vascular systems carrying different concentrations of oxygen and constitute distinct functional units. The aim of this study was to assess the expression of the phenobarbital-inducible cytochrome P-450 b,e genes in hepatocytes of the right and left fetal liver lobes in mice. Northern-blot analysis using [32P]cDNAs and quantitative dot-blot hybridization were performed to assess the size and levels of these mRNAs in the right and left fetal liver lobes. In fetal mice, the levels of cytochrome P-450, b,e mRNAs were higher in the left than in the right fetal liver lobe. During the last days of gestation and in the immediate postnatal period, the levels of liver cytochrome P-450 b,e mRNAs increased predominantly in the left liver lobe. In contrast, the levels of albumin and alpha-fetoprotein mRNAs (genes studied to assess the specificity of these findings) were similar in each of functional units of the fetal liver. Phenobarbital induction of cytochromes P-450 b,e mRNAs was not observed in either of the fetal liver lobes. Postnatally, phenobarbital induced these cytochromes similarly in the right and left liver lobes. Therefore, the microenvironment surrounding fetal hepatocytes seems to influence the expression of the cytochrome P-450 b,e genes. This lobar heterogeneity of expression disappears as the pattern of adult liver circulation is attained.

show abstract

Heterogeneous expression of phenobarbital-inducible cytochrome P-450 genes within the hepatic acinus in the rat

Cited by 20 publications

References 25 publications

Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Demonstration by in situ hybridization of the zonal modulation of rat liver cytochrome P-450b and P-450e gene expression after phenobarbital.

Cytochrome p-450 gene expression in the functional units of the fetal liver

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