In vivo metabolism and reaction with dna of the cytostatic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)

doi:10.1016/0006-2952(86)90419-3

Biochemical Pharmacology

Volume 35, Issue 19, 1 October 1986, Pages 3243-3247

https://doi.org/10.1016/0006-2952(86)90419-3 Get rights and content

Abstract

The cytostatic drug dacarbazine [DTIC, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide] is strongly carcinogenic in rats. Bioactivation of DTIC yields a methylating intermediate but the extent of interaction with cellular macromolecules has not previously been reported. Following a single i.p. injection of [¹⁴C-methyl]DTIC, exhalation of ¹⁴CO₂ occurred with a $t_{12} max$ of approximately 2 hr (0.95 mg/kg) and 2.5 hr (95 mg/kg). Of the total radioactivity administered, 8.5% was exhaled as ¹⁴CO₂; 54% was excreted via the urine, predominantly as unchanged DTIC. In liver, kidney and lung, formation of 7-[¹⁴C]methylguanine in DNA and RNA was directly proportional with dose. DNA methylation by a single dose of DTIC (9.8 mg/kg; 5 hr survival time) was highest in liver (35 μmonoles 7-methylguanine/mole guanine), followed by kidney (25 μmoles) and lung (20 μmoles). The remainder tissues showed 7-methylguanine concentrations approximately 50% of those in liver DNA, with the exception of the brain which had a very low extent of DNA modification (~1 μmole/mole guanine). At the specific radioactivity used (48 mCi/mmole), the promutagenic base O⁶-methylguanine was only detectable in liver, kidney, lung, and stomach DNA (0.6–0.8 μmoles/mole guanine). Autoradiographic studies revealed a diffuse distribution of reaction products in rat liver. In contrast, N-nitrosodimethylamine and related carcinogens known to be bioactivated by the hepatic cytochrome P-450 system show a predominantly centrilobular distribution. This difference may be due to the greater stability of proximate carcinogens generated by α-C hydroxylation at one of the methyl groups of DTIC.

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In vivo metabolism and reaction with dna of the cytostatic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)

Abstract

Eur. J. Cancer

Toxicol. appl. Pharmac.

Cancer Lett.

Chem. biol. Interact.

Biochim. biophys. Acta

Cancer Chemother. Rep.

Clin. Pharmac. Ther.

Cancer Chemother. Rep.

Cancer

Cancer Chemother. Rep.

Carcinogenesis

J. natn. Cancer Inst.

Cancer Res.