Single-dose toxicokinetics ofN-nitrosomethylethylamine andN-nitrosomethyl (2,2,2-trideuterioethyl)amine in the rat

Abstract

To investigate the origins of an organotropic shift toward increasing esophageal carcinogenicity and DNA alkylation caused by beta-trideuteration of the hepatocarcinogen, N-nitrosomethylethylamine (NMEA), the single-dose toxicokinetics of NMEA and N-nitrosomethyl(2,2,2-trideuterioethyl)amine (NMEA-d3) has been characterized in 8-week-old male Fischer 344 rats by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 mumol/kg to rats revealed biphasic first order elimination with a terminal half-life of 9.46 +/- 0.69 min for unchanged NMEA and 28.9 +/- 2.4 min for total radioactivity. Extensive conversion to polar metabolites was observed in the chromatograms. The systemic blood clearance and apparent steady-state volume of distribution for unchanged NMEA were 39.9 +/- 4.6 ml/min/kg and 496 +/- 36 ml/kg, respectively. There was negligible plasma protein binding and no detectable NMEA was excreted unchanged in the urine. Larger doses given by gavage indicated a systemic bioavailability of 25 +/- 1%. Similar doses of NMEA-d3 given to other groups of rats revealed no significant differences in any of the toxicokinetic parameters. No N-nitrosomethyl(2-hydroxyethyl)amine was found as a detectable metabolite of NMEA or NMEA-d3 in any of the blood or urine samples which were analyzed. When considered together, the data suggest that previously observed differences in organ specificity for the carcinogens, NMEA and NMEA-d3, are not due to differences in the total amounts of nitrosamine reaching particular tissues, but may have other localized causes such as differences in the enzymes responsible for metabolism which are present in each tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

β-Deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus

“…Kinetic constants for their conversion to the two a-hydroxylation products, acetaldehyde and formaldehyde, by uninduced liver microsomes are summarized in Table II. As was found for the rates of in vivo clearance of NEMA (7), no significant change in K m or V W3X values could be observed on /3-deuteration of the carcinogen.…”

“…We originally speculated that this shift toward the esophagus resulted from an isotopically-induced retardation of /3-hydroxylation during the first pass through the liver following absorption from the gut of the orally-administered carcinogen, but this proved to be incorrect. Detailed pharmacokinetic studies failed to detect any difference between NEMA and NEMA-d 3 in bioavailability or any other pharmacokinetic parameter, nor was any of the /S-hydroxylation product, N-nitrosomethyl^-hydroxyethyl)amine, found in the blood at a detection limit corresponding to 0.3% of the dose (7). Also, the organotropic shift could not be ascribed to altered excretion of unchanged nitrosamine, as neither NEMA nor NEMA-d 3 could be found in the urine at a level of 0.03% of the dose (7).…”

“…[Methyl-14 C]-labeled NEMA-d 3 was synthesized as previously reported (7). Its ultraviolet and chromatographic properties were similar to those for the ethyl-labeled isomeT described in the previous paragraph (radiochemical purity, 98%; chemical purity, 99.5%; isotopic purity at the 2-position, 95.3% deuterium).…”

Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

“…But further studies revealed that the situation is more complex than anticipated. Deuterium substitution may be without influence on activity (Lijinsky & Reuber 1980a;Streeter et al, 1990), change the organotropic carcinogenicity (Turusov et al, 1988), or may even have an inverse effect (Lijinsky & Reuber, 1980b). The absence of an isotope effect in DMPT-d6 has meanwhile also been shown in a carcinogenicity experiment.…”

Theoretical investigation of mono- and bi-function alkylating agents transformed from nitrosodimethylamine derivatives

“…Subsequently, the resulting N-hydroxymethyl-methylnitrosamine (HMMN) proceeds via a demethylation leading to the formation of methyldiazohydroxide, a strong mono-functional alkylating agent which is able to methylate the bases of DNA to form products like O 6 -methylguanine (O 6 -MeG) and 7-methylguanine (7-mGua) [10][11][12]. In contrast to the widely studies on the bioactivities of NDMA from experimental aspects [12][13][14], there is relatively little theoretical investigation of the mechanistic pathway for further transformation of HMMN. In 1987, Poulsen et al [15] proposed both stepwise and concerted mechanisms for this transformation, shown in Scheme 1a by solid line.…”