The normal activity of peroxisomal enzymes generates ROS and reactive nitrogen species as byproducts of metabolism, but peroxisomes also possess mechanisms that participate in the maintenance of redox homeostasis. This work has identified a number of potential CAR-mediated mechanisms. On this basis, a role for oxidative stress in the mechanism of action of these compounds cannot be excluded. To circumvent this problem, we have created a novel oxidative stress reporter mouse where the HO-1 promoter is used to drive the expression of LacZ. Lactate dehydrogenase was used as a loading control. A, Histological appearance of liver sections from treated mice: Effect of a rhodium III complex.

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PB was administered at 0. Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Coverslips were applied using a water-based mounting gel and images were captured using a Zeiss light microscope.

A carcinogenic mechanism involving metabolism to hydroquinones has therefore been proposed. Nongenotoxic carcinogens have compound-specific effects on hepatic heme oxygenase-1 HO-1 reporter induction. A-H, Detection of LacZ in liver sections by histochemical staining.

A-C, Detection of LacZ in liver sections by histochemical staining. Statistical comparison between PB and vehicle groups at each time point: This reporter was therefore not used in the course of this study and will not be discussed further.

Validation of heme oxygenase-1 HO-1 reporter using compounds which induce oxidative stress. Lactate dehydrogenase was used as a loading control. Identification of the molecular source of radicals responsible for DNA damage by peroxisome fameron. The weak induction of Cyp3a would also be consistent with this Fig.


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It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Cameron, Lynsey Chatham, Lesley A. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse.

Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. The compounds chosen were cadmium chloride CdCl 2 and ethoxyquin 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline; EQ. On this basis, a role for oxidative stress in the mechanism of action of these compounds cannot be excluded. Generation of the quinone metabolite has been associated with DNA strand breaks, an effect which is enhanced under redox cycling conditions and blocked by catalase Muller, Enhancement by Wy, a hepatic peroxisome proliferator, of diethylnitrosamine-initiated hepatic tumorigenesis in the rat.

On the basis of the extremely weak induction of oxidative stress by this compound in our studies, such a mechanism would seem implausible.

Genotoxic carcinogens are relatively easy to distinguish by means of tests for DNA damage and mutagenesis, but nongenotoxic carcinogens NGCs induce tumors by various alternative mechanisms and can be difficult to identify, other than through classic rodent bioassays. Dissecting modes of action of non-genotoxic carcinogens in primary camegon hepatocytes.

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Administration of this compound resulted in strong zonal induction of the HO-1 promoter Fig. Oxford University Press is a department of the University of Oxford. The resulting HO-1 reporter loci contain most of the HO-1 gene together with Oxidative stress leading to continuous release of ROS, possibly associated with P induction and activation of nuclear receptors such as the constitutive androstane receptor CARhas been identified as a central feature in the mechanism of action of NGCs Kobliakov, A toxicogenomic approach for the prediction of murine hepatocarcinogenesis using ensemble feature selection.


Microsomal fractions were prepared from frozen liver tissue according to standard procedures. msoo

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Reactions were carried out in triplicate on a real-time polymerase chain reaction machine Applied Biosystems and HO-1 gene expression was calculated in relative to 18S rRNA using the comparative C T method http: Of the compounds tested, only DCB stimulated a response robustly and a slight degree of activation was also observed for TAA, over the respective vehicle controls. A sample of the supernatant from the first centrifugation step lysate was retained.

In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. Regulatory elements in the promoter are shown as follows: Receive exclusive offers and updates from Oxford Academic.