Evaluation of Octamethylcyclotetrasiloxane (D4) as an Inducer of Rat Hepatic Microsomal Cytochrome P450, UDP-Glucuronosyltransferase, and Epoxide Hydrolase: A 28-Day Inhalation Study

McKim, James M.

doi:10.1006/toxs.1997.2398

Cited by 4 publications

(9 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, octamethylcyclotetrasiloxane (D 4 ), a homolog of D 5 had been extensively studied. In rodents, inhalation exposure to D 4 results in dose-related hepatomegaly, transient hepatic hyperplasia, hypertrophy, and induction of hepatic cytochrome P450 enzymes in a fashion similar to phenobarbital (McKim et al, 1998(McKim et al, , 2001). Very limited toxicity data are available on HMDS and D 5 in biological systems.…”

mentioning

confidence: 99%

Metabolites of Hexamethyldisiloxane and Decamethylcyclopentasiloxane in Fischer 344 Rat Urine—A Comparison of a Linear and a Cyclic Siloxane

Varaprath¹,

McMahon²,

Plotzke³

2003

Drug Metabolism and Disposition

View full text Add to dashboard Cite

were obtained using a high-pressure liquid chromatography (HPLC) system equipped with a radioisotope detector. The metabolite elution was carried out on a C 18 column using an acetonitrile/ water mobile phase. The structural assignments were based on GC-MS analysis of the tetrahydrofuran extract of urine containing the metabolites. Some of the metabolites in the extracts were first protected with trimethylsilyl groups prior to GC-MS analysis using bis(trimethylsiloxy)trifluoroacetamide or highly purified hexamethyldisiloxane. Hexamethyldisiloxane (MM, HMDS 1 ), the smallest member of the polydimethylsiloxane polymers, and decamethylcyclopentasiloxane (D 5 ), a cyclic siloxane are colorless volatile fluids. MM is quite volatile with a vapor pressure of 42.2 mm Hg at 25°C and a boiling point of 100°C (Flanningam, 1986). D 5 is relatively less volatile with a vapor pressure of 2 mm Hg at 50°C and a boiling point of 210°C. The aqueous solubilities of MM and D 5 are 930 and 17 ppb, respectively (Varaprath et al., 1996). The primary use of MM and D 5 is as intermediates in the manufacturing of high molecular weight siloxane polymers. MM and D 5 also find use as vehicles or ingredients in a wide range of consumer product formulations (Cameron et al., 1986) since they have several favorable properties such as low surface tension, adequate evaporation rate, lack of odor, high degree of compatibility with many consumer product ingredients, and low toxicity. Typical examples of applications include moisturizing creams, lotions, bath oils, colognes, shaving products, and perfumes. Besides these product applications, they are also used as cleaners, lubricants, and penetrating oils.The rigorously purified MM (Dow Corning OS-10, purity Ͼ99.9%) is one of the many ozone-safe volatile methylsiloxanes that is exempt from federal volatile organic compound regulations and hence is accepted as an alternative for other organic solvents. Another important industrial use of MM is as a chain-terminating agent in siloxane polymerizations. The use of MM and D 5 in various product formulations necessitated conducting chemical and environmental fate/effects tests of them.Potential human exposure to MM and D 5 can result at the work place during the manufacturing process, as well as through the normal use of consumer products that contain them. Only sparse toxicological information is available on these siloxanes since they are believed to be relatively inert and of low toxicity. However, octamethylcyclotetrasiloxane (D 4 ), a homolog of D 5 had been extensively studied. In rodents, inhalation exposure to D 4 results in dose-related hepatomegaly, transient hepatic hyperplasia, hypertrophy, and induction of hepatic cytochrome P450 enzymes in a fashion similar to phenobarbital (McKim et al., 1998(McKim et al., , 2001). Very limited toxicity data are available on HMDS and D 5 in biological systems. In a 13-week subchronic MM whole-body inhalation, renal histopathology consis-1 Abbreviations used are: MM, (HMDS) hexamethyldisiloxane; D 5 , decame...

show abstract

mentioning

confidence: 99%

Metabolites of Hexamethyldisiloxane and Decamethylcyclopentasiloxane in Fischer 344 Rat Urine—A Comparison of a Linear and a Cyclic Siloxane

Varaprath¹,

McMahon²,

Plotzke³

2003

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Previous studies have indicated that treatment of young female rats with D4 and D5 results in an increase in the liver to body weight ratio [4,5,7]. In the current study the effects of D4 on the liver mass of young, pregnant, and mature female rats were also investigated.…”

Section: Liver/body Weight Ratiosmentioning

confidence: 92%

“…Treatment of rats with D4 either by inhalation [5] or gavage [7] has been reported to induce CYP2B isoforms in both male and female rat liver. These studies were carried out utilizing treatment of young adult rats.…”

Section: Induction Of Cyp2b1/2mentioning

confidence: 99%

“…Recently, D4 and decamethylpentacyclosiloxane (D5) have been reported to increase the activity and immunoreactive protein of several drug-metabolizing enzymes including cytochromes P450 (CYP), epoxide hydrolase, and NADPH CYP450 oxidoreductase [5,7]. Microsomal mono-oxygenase systems containing CYPs have an important role in the metabolism of endogenous substrates as well as in the detoxification of many drugs and xenobiotics and in the activation of environmental agents to biologically deleterious forms [10].…”

Section: Introductionmentioning

confidence: 99%

“…DMCS were initially believed to be biologically inert; however, several DMCS have been reported to be biologically active. D4 and D5 have been demonstrated to exhibit a phenobarbital (PB)-like effect in their ability to induce metabolic enzymes and enhance cell proliferation [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of age and pregnancy on cytochrome P450 induction by octamethyltetracyclosiloxane in female Sprague‐Dawley rats

Falany

2005

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Dimethylcyclosiloxanes (DMCS) are components of silicone gel containing implants and are known inducers of human drug metabolizing enzymes. The effects of the major DMCS, octamethyltetracyclosiloxane (D4) on cytochrome P450 (CYP) induction were examined in young adult, mature, and pregnant female Sprague-Dawley rats. Also, the ability of D4 administered to pregnant dams to affect CYP expression in fetal liver was examined. Female young, mature, and pregnant Sprague-Dawley rats were administered 0, 5, 20, and 100 mg/kg D4 daily by gavage for 8 days. Liver microsomal CYP (CYP2B, CYP3A, CYP1A) concentrations were evaluated by Western blots using specific antisera, and CYP activities were assayed using CYP selective assays. D4 treatment resulted in a significant induction of CYP2B and CYP3A isoforms. CYP induction was dose and age dependent. A comparison of the inducibility of CYP3A protein by D4 in rats from different age groups showed that the degree of increase was the highest in the pregnant rats at doses of 20 mg/kg D4 or higher. The mature rats had a lesser degree of responsiveness than did the young rats at the dose of 100 mg/ kg D4. Significant increases in CYP2B immunoreactive protein concentrations were observed in young and mature rats given D4 at doses >5 mg/kg and in pregnant rats at doses >20 mg/kg. Maximal CYP2B induction detected with blotting was more than 90-fold in mature rats; however, no significant changes were detected in CYP1A expression. There was a 20% increase of liver to body weight ratio in the mature rats treated with 100 mg/kg D4. D4 has different inductive properties in female rats of different ages and reproductive status. Also, D4 administered to the pregnant dam is capable of inducing CYP expression in fetal liver as well as decreasing fetal body weight.

show abstract

Building a Tiered Approach to In Vitro Predictive Toxicity Screening: A Focus on Assays with In Vivo Relevance

McKim¹

2010

CCHTS

202

190

View full text Add to dashboard Cite

One of the greatest challenges facing the pharmaceutical industry today is the failure of promising new drug candidates due to unanticipated adverse effects discovered during preclinical animal safety studies and clinical trials. Late stage attrition increases the time required to bring a new drug to market, inflates development costs, and represents a major source of inefficiency in the drug discovery/development process. It is generally recognized that early evaluation of new drug candidates is necessary to improve the process. Building in vitro data sets that can accurately predict adverse effects in vivo would allow compounds with high risk profiles to be deprioritized, while those that possess the requisite drug attributes and a lower risk profile are brought forward. In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity. However, when used in a prospective manner, they have not been highly predictive of in vivo toxicity. Therefore, the issue may not be how to collect in vitro toxicity data, but rather how to translate in vitro toxicity data into meaningful in vivo effects. This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

show abstract

Evaluation of Octamethylcyclotetrasiloxane (D4) as an Inducer of Rat Hepatic Microsomal Cytochrome P450, UDP-Glucuronosyltransferase, and Epoxide Hydrolase: A 28-Day Inhalation Study

Cited by 4 publications

References 42 publications

Metabolites of Hexamethyldisiloxane and Decamethylcyclopentasiloxane in Fischer 344 Rat Urine—A Comparison of a Linear and a Cyclic Siloxane

Metabolites of Hexamethyldisiloxane and Decamethylcyclopentasiloxane in Fischer 344 Rat Urine—A Comparison of a Linear and a Cyclic Siloxane

Effects of age and pregnancy on cytochrome P450 induction by octamethyltetracyclosiloxane in female Sprague‐Dawley rats

Building a Tiered Approach to In Vitro Predictive Toxicity Screening: A Focus on Assays with In Vivo Relevance

Contact Info

Product

Resources

About