Distribution of urethane and its binding to dna, rna, and protein in sencar and balb/c mice following oral and dermal administration

Abstract

Urethane produces threefold more skin papillomas when administered orally than dermally in SENCAR mice, a strain susceptible to tumorigenesis. To better understand the relation of distribution to the initiation stage, [14C]urethane (0.10 mg/kg, 2.5 muCi/25 g) was administered orally and dermally to male SENCAR and BALB/c mice. Absorption of urethane was greater in the first hour in SENCAR mice by both routes, as indicated by more label in the liver, lung, and stomach than found in these tissues in BALB/c mice. 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 h in the SENCAR mice when compared to BALB/c mice. Binding of [14C]urethane (0.062 mg/g body weight, 20 microCi/20 g body weight) to DNA, RNA, and protein 6 h after oral administration varied with tissue (liver greater than stomach greater than skin = lung) but did not differ with strain. Binding to DNA in skin, lung, and stomach, RNA in stomach, and protein in stomach and liver after 48 h were significantly higher in SENCAR mice than in BALB/c mice. Dermal application of [14C]urethane resulted in severalfold higher binding to liver DNA of SENCAR mice than BALB/c mice, but DNA binding was comparable in other tissues after 6 h. At 48 h after dermal application, significantly higher levels of [14C]urethane remained bound to skin DNA, RNA, and protein in BALB/c mice, although all values were lower than at 6 h after treatment. Differences in the distribution and binding of urethane probably do not account for the discrepancies in tumor sensitivity. Liver DNA hydrolysates were examined after 48 h. Thin-layer chromatography showed little incorporation of the 14C into the normal deoxyribonucleotide or deoxyribonucleoside bases, and no modified bases were apparent. Radioactivity was present in the fraction that remained at the origin and was consistent with a dinucleotide fragment resistant to phosphodiesterase cleavage, such as a phosphotriester.