Evaluation of octamethylcyclotetrasiloxane (D4) as an inducer of rat hepatic microsomal cytochrome P450, UDP-glucuronosyltransferase, and epoxide hydrolase: a 28-day inhalation study. 1998

J M McKim, and P C Wilga, and G B Kolesar, and S Choudhuri, and A Madan, and L W Dochterman, and J G Breen, and A Parkinson, and R W Mast, and R G Meeks
Dow Corning Corporation, Health and Environmental Sciences, Midland, Michigan 48686, USA.

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.

UI MeSH Term Description Entries
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009251 NADPH-Ferrihemoprotein Reductase A flavoprotein that catalyzes the reduction of heme-thiolate-dependent monooxygenases and is part of the microsomal hydroxylating system. EC 1.6.2.4. Cytochrome P-450 Reductase,Ferrihemoprotein P-450 Reductase,NADPH Cytochrome P-450 Oxidoreductase,NADPH Cytochrome P-450 Reductase,NADPH Cytochrome c Reductase,Cytochrome P-450 Oxidase,Cytochrome P450 Reductase,Ferrihemoprotein P450 Reductase,NADPH Cytochrome P450 Oxidoreductase,NADPH Cytochrome P450 Reductase,NADPH-Cytochrome P450 Reductase,NADPH-P450 Reductase,Cytochrome P 450 Oxidase,Cytochrome P 450 Reductase,Ferrihemoprotein P 450 Reductase,NADPH Cytochrome P 450 Oxidoreductase,NADPH Cytochrome P 450 Reductase,NADPH Ferrihemoprotein Reductase,NADPH P450 Reductase,Oxidase, Cytochrome P-450,P-450 Oxidase, Cytochrome,P450 Reductase, Cytochrome,P450 Reductase, NADPH-Cytochrome,Reductase, Cytochrome P-450,Reductase, Cytochrome P450,Reductase, Ferrihemoprotein P-450,Reductase, Ferrihemoprotein P450,Reductase, NADPH-Cytochrome P450,Reductase, NADPH-Ferrihemoprotein,Reductase, NADPH-P450
D011916 Rats, Inbred F344 An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes. Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D004851 Epoxide Hydrolases Enzymes that catalyze reversibly the formation of an epoxide or arene oxide from a glycol or aromatic diol, respectively. Epoxide Hydrase,Epoxide Hydrases,Epoxide Hydratase,Epoxide Hydratases,Epoxide Hydrolase,9,10-Epoxypalmitic Acid Hydrase,Microsomal Epoxide Hydrolase,Styrene Epoxide Hydrolase,9,10 Epoxypalmitic Acid Hydrase,Acid Hydrase, 9,10-Epoxypalmitic,Epoxide Hydrolase, Microsomal,Epoxide Hydrolase, Styrene,Hydrase, 9,10-Epoxypalmitic Acid,Hydrase, Epoxide,Hydrases, Epoxide,Hydratase, Epoxide,Hydratases, Epoxide,Hydrolase, Epoxide,Hydrolase, Microsomal Epoxide,Hydrolase, Styrene Epoxide,Hydrolases, Epoxide
D005260 Female Females
D000276 Adjuvants, Immunologic Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (Freund's adjuvant, BCG, Corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Immunoactivators,Immunoadjuvant,Immunoadjuvants,Immunologic Adjuvant,Immunopotentiator,Immunopotentiators,Immunostimulant,Immunostimulants,Adjuvant, Immunologic,Adjuvants, Immunological,Immunologic Adjuvants,Immunological Adjuvant,Adjuvant, Immunological,Immunological Adjuvants
D000280 Administration, Inhalation The administration of drugs by the respiratory route. It includes insufflation into the respiratory tract. Drug Administration, Inhalation,Drug Administration, Respiratory,Drug Aerosol Therapy,Inhalation Drug Administration,Inhalation of Drugs,Respiratory Drug Administration,Aerosol Drug Therapy,Aerosol Therapy, Drug,Drug Therapy, Aerosol,Inhalation Administration,Administration, Inhalation Drug,Administration, Respiratory Drug,Therapy, Aerosol Drug,Therapy, Drug Aerosol

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