N-Methylation and quaternization of pyridine in vitro by rabbit lung, liver and kidney N-methyltransferases: an S-adenosy1-L-methioninedependent reaction

Damani, L. A.; Shaker, Monier; Crooks, Peter A.; Godin, C.; Nwosu, Chukwuemeka G.

doi:10.3109/00498258609043554

Cited by 12 publications

(3 citation statements)

References 13 publications

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“…This metabolite subsequently has been observed in vivo in several animal species (204)(205)(206)(207)(208). The N-methylation of pyridine is catalyzed by cytosolic enzymes expressed in liver, lung, and kidney (209). In all cases, S-methyladenosinylmethionine is the methyl donor.…”

Section: Tetrahydroisoquinolines and Tetrahydro-β-carbolinementioning

confidence: 95%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1

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Section: Tetrahydroisoquinolines and Tetrahydro-β-carbolinementioning

confidence: 95%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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“…Pyridine N-methylation of AZD0328 (M2) was identified as a dog specific metabolite, not observed in human or other preclinical species. Pyridine N-methyltransferase activities have been previously reported for methylation of pyridine and nicotinamide (Damani et al, 1986;Rini et al, 1990;Parsons et al, 2002), however, the species difference of cytosolic methyltransferase remains to be characterized.…”

Section: Discussionmentioning

confidence: 98%

In vitrometabolism of α7 neuronal nicotinic receptor agonist AZD0328 and enzyme identification for itsN-oxide metabolite

Zhou

Zhang

et al. 2011

Xenobiotica

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1. AZD0328 was pharmacologically characterized as a α7 neuronal nicotinic receptor agonist intended for treatment of Alzheimer's disease. In vitro AZD0328 cross species metabolite profile and enzyme identification for its N-oxide metabolite were evaluated in this study. 2. AZD0328 was very stable in the human hepatocyte incubation, whereas extensively metabolized in rat, dog and guinea pig hepatocyte incubations. The N-oxidation metabolite (M6) was the only metabolite detected in human hepatocyte incubations, and it also appeared to be the major in vitro metabolic pathway in a number of preclinical species. In addition, N-glucuronide metabolite of AZD0328 was observed in human liver microsomes. 3. Other metabolic pathways in the preclinical species include hydroxylation in azabicyclo octane or furopyridine part of the molecule. Pyridine N-methylation of AZD0328 (M2) was identified as a dog specific metabolite, not observed in human or other preclinical species. 4. Multiple enzymes including CYP2D6, CYP3A4/5, FMO1 and FMO3 catalyzed AZD0328 metabolism. The potential for AZD0328 to be inhibited clinically by co-administered drugs or genetic polymorphism is relative low.

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“…This stability is due mainly to the electronegativity of nitrogen that makes the ring electron deficient and, therefore, less prone to electron abstraction. Other reports on metabolism of pyridine include N-oxidation, N-methylation (Damani et al, 1986), and N-glucronidation (Lin, 1999;Wiener et al, 2004). On the other hand, few cases of ring opening of pyridine have been reported, including microbial ring opening of pyridine derivatives (Kaiser et al, 1996), the formation of muconaldehyde from benzene mediated by cytochrome P450 (Latriano et al, 1986), and the formation of E-2-(acetaminomethylene) succinate from a vitamin B6 degradant (McCulloch et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

Khojasteh

Qin

et al. 2014

Drug Metab Dispos

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Vismodegib (Erivedge, GDC-0449) is a first-in-class, orally administered small-molecule Hedgehog pathway inhibitor that is approved for the treatment of advanced basal cell carcinoma. Previously, we reported results from preclinical and clinical radiolabeled mass balance studies in which we determined that metabolism is the main route of vismodegib elimination. The metabolites of vismodegib are primarily the result of oxidation followed by glucuronidation. The focus of the current work is to probe the mechanisms of formation of three pyridine ring-cleaved metabolites of vismodegib, mainly M9, M13, and M18, using in vitro, ex vivo liver perfusion and in vivo rat studies. The use of stable-labeled ( 13 C 2 , 15 N)vismodegib on the pyridine ring exhibited that the loss of carbon observed in both M9 and M13 was from the C-6 position of pyridine. Interestingly, the source of the nitrogen atom in the amide of M9 was from the pyridine. Evidence for the formation of aldehyde intermediates was observed using trapping agents as well as 18 O-water. Finally, we conclude that cytochrome P450 is involved in the formation of M9, M13, and M18 and that M3 (the major mono-oxidative metabolite) is not the precursor for the formation of these cleaved products; rather, M18 is the primary cleaved metabolite.

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N-Methylation and quaternization of pyridine in vitro by rabbit lung, liver and kidney N-methyltransferases: an S-adenosy1-L-methioninedependent reaction

Cited by 12 publications

References 13 publications

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

In vitrometabolism of α7 neuronal nicotinic receptor agonist AZD0328 and enzyme identification for itsN-oxide metabolite

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

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