Zonation of metabolism and gene expression in liver

Jungermann, Kurt

doi:10.1007/bf01454004

Cited by 130 publications

(112 citation statements)

References 86 publications

(53 reference statements)

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“…In this concept, the liver consists of a collection of interdigitating, functionally distinct periportal (or upstream) and pericentral (or downstream) domains: "metabolic zonation." 1 The concept of upstream and downstream populations of hepatocytes further predicts a direct relationship between the enzymic phenotype of a hepatocyte and its position on the porto-central axis (Fig. 1).…”

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confidence: 97%

Stereological measurement of porto-central gradients in gene expression in mouse liver

et al. 2004

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The liver is thought to consist of lobules, numerous repeating, randomly oriented units. Within these lobules, genes are expressed in gradients along the porto-central axis, which spans the distance between portal and central veins. We have developed a robust stereological method to map all points in an image to their position on this porto-central axis. This approach is based on the distribution of well-characterized periportal and pericentral enzymes, which are visualized on sections preceding and following the section of interest. Because expression of the model genes phosphoenolpyruvate carboxykinase and ornithine aminotransferase declines gradually with increasing distance from the portal vein and central vein, respectively, these genes can be used to prepare images with topographical information without any assumption about the shape of the hepatic unit, or about the direction or shape of the gradient to be determined. The "relative distance" image is a 2-dimensional image that accurately maps the relative position of hepatocytes on the porto-central axis in 3-dimensional space. It is superimposed on the serial section under investigation to relate local staining density to position on the porto-central axis and obtain the gene expression gradient. The method was used to determine the expression gradient of 2 periportal and 2 pericentral enzymes and their response to fasting. The "total distance" image was used to measure the length of the porto-central axis, which was approximately 210 m in mice and found to decrease 13% after 1 day of starvation. The method can be applied to any tissue component that can be stained quantitatively. (HEPATOLOGY 2004;39:343-352.)

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confidence: 97%

Stereological measurement of porto-central gradients in gene expression in mouse liver

et al. 2004

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“…In the presence of substrates, this polymerization mechanism may preserve the catalytically significant P450 isoforms and facilitate the aggregation of P450 isoforms that lack substrate, thereby decreasing their levels (Kimzey et al, 2003). It has been reported that P450s are nonuniformly distributed in the endoplasmic reticulm, forming clusters rather than possessing a continuous distribution (Matsuura et al, 1978), whereas other reviews have suggested the existence of zonal differences in P450 distribution within the liver (Jungermann, 1995;Oinonen and Lindros, 1998). These differences in distribution would be expected to promote P450-P450 interactions.…”

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confidence: 99%

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

Subramanian

Tam²,

Zheng³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Cytochromes P450 (P450s) interact with redox transfer proteins, including P450 reductase (CPR) and cytochrome b 5 (b5), all being membrane-bound. In multiple in vitro systems, P450-P450 interactions also have been observed, resulting in alterations in enzymatic activity. The current work investigated the effects and mechanisms of interaction between CYP2C9 and CYP3A4 in a reconstituted system. CYP2C9-mediated metabolism of S-naproxen and S-flurbiprofen was inhibited up to 80% by coincubation with CYP3A4, although K m values were unchanged. Increasing CYP3A4 concentrations increased the degree of inhibition, whereas increasing CPR concentrations resulted in less inhibition. Addition of b5 only marginally affected the magnitude of inhibition. In contrast, CYP2C9 did not alter the CYP3A4-mediated metabolism of testosterone. The potential role of the hydrophobic N terminus on these interactions was assessed by incubating truncated CYP2C9 with full-length CYP3A4, and vice versa. In both cases, the inhibition was fully abolished, indicating an important role for hydrophobic forces in CYP2C9-CYP3A4 interactions. Finally, a CYP2C9/CYP3A4 heteromer complex was isolated by coimmunoprecipitation techniques, confirming the physical interaction of the proteins. These results show that the N-terminal membrane binding domains of CYP2C9 and CYP3A4 are involved in heteromer complex formation and that at least one consequence is a reduction in CYP2C9 activity.Cytochromes P450 (P450s) are the primary oxidative enzymes responsible for the metabolism of xenobiotics by humans and animals (Guengerich, 2006). P450s can oxidize structurally diverse substrates ranging from small hydrocarbons to large molecules such as cyclosporine. P450s function by transferring electrons via a P450 catalytic pathway, wherein the first electron is transferred to the P450 via cytochrome NADPH P450 reductase (CPR) and the second electron is transferred via either CPR or cytochrome b 5 (b5) (Guengerich, 2002). Inefficiencies in the catalytic pathway, in part, govern the rate of transformation. P450s and CPR are bound to the cell membrane via a hydrophobic N terminus, whereas b5 is bound via its C terminus, each terminal being composed of 30 to 60 amino acids (Szczesna-Skorupa and Kemper, 2008). This hydrophobic region also contributes to protein aggregation, resulting in the formation of high molecular weight polymers in membranes and reconstituted systems (SzczesnaSkorupa and Kemper, 2008). Considering that P450s and CPR, and P450s and b5 interact within the cell membrane, P450-P450 interactions also appear conceivable. Indeed, in vitro evidence of P450-P450 interactions have been observed in several studies, including interactions of human CYP2C9-CYP2C19, rabbit CYP1A2-CYP2B4, rabbit CYP1A2-CYP2E1, human CYP3A4-CYP1A1, human CYP3A4-CYP1A2, and human CYP2C9-CYP2D6 (Cawley et al., 1995;Yamazaki et al., 1997;Backes et al., 1998;Backes and Cawley, 1999;Kelley et al., 2005Kelley et al., , 2006Subramanian et al., 2009). Substrate-dependent activation o...

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“…Therefore our work in type 1 diabetes model reproduces those of periportal GK overexpression (Ferre, 1996a) and those of liver homogeneous GK overexpression (Morral, 2002(Morral, , 2007 in terms of glycaemia. However, our results on lipid metabolism are more deleterious, probably because perivenous hepatocytes have higher lipogenic potential than periportal hepatocytes (Jungermann, 1995). All in all, our review of the literature together with our own results on the subject will convey that pGK-overexpression in the liver, independent of zonation, will result in changes in glycaemia but with the risk of non-desirable lipid alterations and insulin resistance.…”

Section: Wwwintechopencommentioning

confidence: 58%

“…c. Promoter that directs transgene expression can affect two important variables. On one hand, taking into account the metabolic hepatic zonation concept (Jungermann, 1995), the promoter determines which set of hepatocytes express the transgene. It is well known that physiological GK expression predominates in the perivenous area of the liver (Moorman, 1991;Jungerman, 1995& Jungerman, 2000.…”

Section: Wwwintechopencommentioning

confidence: 99%