EFFECT OF ROUTE OF ADMINISTRATION ON URETHANE DISPOSITION IN MOUSE STRAINS OF DIFFERING SENSITIVITIES TO TUMOR INDUCTION

ANTHONY ANDREA FOSSA, Purdue University

Abstract

In the initiation-promotion assay for mouse skin tumorigenesis, the response depends on both the route of administration and mouse strain. Urethane produces 3-fold more papillomas when administered orally than dermally in SENCAR mice, a strain developed for its susceptibility to tumorigenesis. The differences in response make the interpretation of the initiation-promotion assay for tumorigenesis difficult. To better understand the relationship of absorption, distribution, metabolism and binding to the initiation stage, ('14)C-urethane (100 mg/kg, 2.5 uCi/25 g) was administered orally and dermally to male mice of both strains. Absoprtion of urethane was greater in the first hour in SENCAR mice by both routes as indicated by more label in the liver, lung, stomach and skin. These differences were not observed at later time periods after oral administration. Following dermal application, higher levels were maintained in the liver, lungs and stomach through 48 hours in the SENCAR mice. Binding of ('14)C-urethane to macromolecules was examined by administering urethane (62 mg/kg, 50 uCi/20 g) orally and dermally to both mouse strains. Binding of ('14)C to DNA, RNA and protein 6 hours after oral administration varied with tissue (liver > stomach > skin = lung) but did not differ with strain. Binding to DNA, RNA and protein after 48 hours was significantly higher in SENCAR mice than in BALB/c mice. The skin DNA from BALB/c mice had significantly more ('14)C-label than the SENCAR strain 48 hours after dermal application although the latter had more label bound to the liver DNA. Attempts to examine the binding of urethane to macromolecules after metabolic alteration with SKF-525A or phenobarbital were not definitive. Upon elution of the deoxyribonucleotides and deoxyribonucleosides isolated from the liver DNA of SENCAR mice, the label was not incorporated into the normal bases but rather a phosphotriester may be formed which might block the cleavage of the 3'-5' phosphate linkage of DNA. This adduct may prevent endogenous nucleases from repairing the damaged DNA and allow expression for tumor formation. Ethylene oxide as a theoretical metabolite of urethane was proposed as a potential carcinogen formed, but chromatography studies with isolated nucleotides indicated dissimilar elution patterns between ethylene oxide and urethane.

Degree

Ph.D.

Subject Area

Pharmacology

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