Abstract
The effects of phenobarbital, trans-stilbene oxide, and 3-methylcholanthrene on epoxide hydrolase (EC 3.3.2.3) within centrilobular, midzonal, and periportal hepatocytes were investigated employing rabbit anti-serum produced against rat hepatic microsomal epoxide hydrolase in unlabeled antibody peroxidase-anti-peroxidase and indirect fluorescent antibody-staining techniques. In livers of control rats, midzonal and periportal hepatocytes bound the anti-epoxide hydrolase to similar extents while centrilobular hepatocytes bound approximately 25% more antibody. 3-Methylcholanthrene did not cause significant alterations in immunohistochemical staining for epoxide hydrolase within any region of the liver lobule, whereas phenobarbital and trans-stilbene oxide produced significant alterations in both the intensity and pattern of intralobular staining for the enzyme. After 4 days of phenobarbital pretreatment, anti-epoxide hydrolase binding to hepatocytes was slightly, but significantly, elevated, especially within midzonal regions. After 7 days of phenobarbital pretreatment, anti-epoxide hydrolase binding was increased by approximately 65% within midzonal regions and by approximately 41 and 24%, respectively, within centrilobular and periportal regions. In livers of trans-stilbene oxide-pretreated rats, anti-epoxide hydrolase binding was increased by approximately 80% within both the midzonal and periportal regions and by approximately 43% within centrilobular regions. These immunohistochemical findings demonstrate that phenobarbital and trans-stilbene oxide both induce epoxide hydrolase nonuniformly within the liver lobule. However, while phenobarbital induces the enzyme to the greatest extent within midzonal hepatocytes and to the least extent within periportal hepatocytes, trans-stilbene oxide induces epoxide hydrolase equally within midzonal and periportal hepatocytes.
Highlights
The effects of phenobarbital, trans-stilbene oxide, nobiotics can be inactivated by conversion totheircorreand 3-methylcholanthrene on epoxide hydrolase
The hydration of epoxides leads to hepatocytes were investigatedemploying rabbit anti- detoxication of these reactive metabolites, certainisoenzymes serum produced against rat hepatic microsomal epox- of cytochrome P-450, especially those induced by polycyclic ide hydrolase in unlabeled antibody peroxidase-anti- aromatichydrocarbons, may further oxidativelymetabolize peroxidase and indirect fluorescent antibody-staining trans-dihydrodiols toyield highly mutagenic and carcinogenic techniques
Therelationship between iportal hepatocytes bound the anti-epoxide hydrolase epoxide-generating cytochromes P-450-containing monooxyto similarextentswhilecentrilobular hepatocytes bound approximately 25% more antibody. 3-Methylcholanthrene did not cause significant alterations in immunohistochemical staining for epoxide hydrolase within any regionof the liver lobule, whereas phenobarbital and trans-stilbeneoxide produced significant genase enzyme systems and epoxide hydrolase appears to be one of thecriticalfactors regulating theintracellularand intratissue levels of potentially hazardous epoxide metabolites
Summary
Centrilobular and midzonalregions of the liver lobule (Fig. 5A). Hepatocellular damagewasproduced by this dose of Localization of Epoxide Hydrolase within Livers of Control trans-stilbene oxide in both Holtzman and Sprague-Dawley and Xenobiotic-pretreated Ruts-Utilizing both unlabeled an- rats but was rarely apparent when the xenobiotic was admintibody peroxidase-antiperoxidaseand indirectfluorescent an- istered at a dose of 300 mg/kg/day (Fig. 5B). Occasional bene oxide pretreatment resulted in increases of 42, 80, and nuclei were observed to be circumscribed by dense rings of 77% in anti-epoxide hydrolase binding to centrilobular, midstain, indicating association of the enzyme with the nuclear zonal, and periportal hepatocytes,respectively(Fig. 4), and envelope. These findings are, consistent with previous caused hepatocytes within the three regions of the lobule to observations madeby this laboratory (13,14) and by Bentley bind the anti-epoxidehydrolase to similar extents(Fig. 3). A moredetailed analysisof the vation was verified by microfluorometric analysis (Figs. 3and intralobular distributionof immunohistochemical stainingfor 4) which demonstratedthat3-methylcholanthrene did not epoxide hydrolase was obtained by utilizing microfluorometry producesignificant alterations ( p < 0.05) inanti-epoxide
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