Glucuronidation of 4-[(Hydroxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone, a Metabolically Activated Form of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, by Phenobarbital-Treated Rats

Abstract

In the rat, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung tumors independent of the route of administration. To exert its carcinogenic potential, NNK must be metabolically activated. Like most nitrosamines NNK is activated by alpha-hydroxylation. The striking tissue specificity of tumor induction by nitrosamines has been primarily attributed to the efficient alpha-hydroxylation of a particular nitrosamine by its target tissue. Two other factors which may contribute to this are the following: the relative capacity of different tissues to detoxify the alpha-hydroxynitrosamine and the preferential uptake of the active metabolite by the target tissue. In the present study we report the characterization of the O-glucuronide of 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone (alpha-hydroxymethylNNK-Gluc). The formation of this glucuronide could either serve as a detoxification pathway or provide a stable transport form of the alpha-hydroxylated metabolite. In addition, the metabolism of NNK to a glucuronide of the alpha-hydroxynitrosamine provides the first definitive evidence for the formation of alpha-hydroxymethylNNK. alpha-HydroxymethylNNK-Gluc was present in the urine of rats treated with phenobarbital (PB) and NNK. It was also formed by hepatocytes from PB-treated rats, accounting for 4% of the total metabolites in the media following incubation with 1 microM NNK. The data that support the identity of this metabolite as alpha-hydroxymethylNNK-Gluc are as follows. (1) Incubation of this metabolite with beta-glucuronidase resulted in the quantitative release of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), the decomposition product of alpha-hydroxymethylNNK.(ABSTRACT TRUNCATED AT 250 WORDS)

Transport of the β-O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1)

“…Low levels of two additional glucuronide conjugates of NNK are also formed during metabolism, ␣-hydroxymethyl NNK-glucuronide, and HPB-glucuronide (Fig. 1), but whether or not they are MRP1 substrates remains to be determined (53).…”

Tissue distributions of 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide, a stable form of reactive intermediate produced from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in the rat

“…HO-Methyl NNK glucuronide was first identified in urine after dosing of NNK to PB-pretreated rats (Murphy et al, 1995). The same group also reported the identification of the glucuronide in hepatocytes prepared from PB-or 3-MC-pretreated rats (Murphy et al, 1997).…”

“…The differences in the organ-specific metabolism of NNK may be crucial for tissue selectivity in NNK-induced carcinogenesis. Murphy et al (1995Murphy et al ( , 1997 proposed that the formation of HO-methyl NNK glucuronide could serve as a transport form of the active metabolite of NNK. HO-Methyl NNK glucuronide is relatively stable so that it could travel to extrahepatic tissues.…”

“…Other possible inactivation pathways for NNK and NNAL are the formation of their corresponding glucuronides. At present, four NNK-and NNAL-related glucuronides have been reported (Morse et al, 1990;Murphy et al, 1995Murphy et al, , 1997Hecht, 1998;Stepanov and Hecht, 2005) (Fig. 1): 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (HO-methyl NNK) glucuronide, HPB glucuronide, NNAL N-glucuronide and NNAL O-glucuronide.…”

“…In the case of the aforementioned NNK-and NNAL-related glucuronides, their formation is essentially a detoxification reaction, but, as an exception, HO-methyl NNK glucuronide not only can play a role in detoxification but can also be involved in the activation process (Hecht, 1998). Although principally HO-methyl NNK glucuronide formation is a detoxification reaction, the glucuronide could be either excreted into urine or transported to other organs where it may be cleaved by β-glucuronidase followed by release of a reactive intermediate that can covalently bind to DNA or protein (Murphy et al, 1995(Murphy et al, , 1997. In the present study, we investigated the tissue distribution of HO-methyl NNK glucuronide in the phenobarbital (PB)-pretreated rat.…”