Search PubMed⌕ Search

Biomedical subjects

N Castagnoli

Publications and source records attributed to N Castagnoli.

At least 55 records · Page 3Linked to original sources
PubMed1997

Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes.

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 as 40-50) 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

Amines↗
PubMed1997

Inhibition of monoamine oxidase contributes to the protective effect of 7-nitroindazole against MPTP neurotoxicity.

The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Effect of the haloperidol tetrahydropyridine metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine on dopamine receptor and transporter binding. A nonhuman primate 123I-iodobenzamide and 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane single photon emission computed tomographic study.

Researching the biological activities and toxicities of metabolites of drugs is of growing importance and has received increasing attention during the last decade in order to gain a better understanding of the efficacy and safety profile of drugs in clinical use. HPTP (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3, 6-tetrahydropyridine, CAS 52669-92-8), the tetrahydropyridine metabolite of the classical neuroleptic, haloperidol (CAS 52-86-8), has recently been the focus for further understanding the well-known side effect profile of haloperidol. The current study was aimed at investigating the effect of HPTP treatment on dopamine receptor and transporter binding in the nonhuman primate, i.e. the baboon Papio ursinus. The study was performed using the dopamine receptor ligand, 123-I-iodobenzamide (IBZM) and the dopamine transporter ligand, [123]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) in planar scintigraphy and single photon emission computed tomographic (SPECT) protocols. Dopamine receptor binding in the striatum was measured from the time activity curves by calculating the IBZM ratios of the basal ganglia to frontal cortex and of the basal ganglia to cerebellum. 99mTc-HMPAO (hexamethylpropylene amine oxime) SPECT detected no changes in striatal perfusion during HPTP treatment. The transporter binding was measured by dynamic imaging of the basal ganglia, frontal cortex and cerebellum using beta-CIT. IBZM dopamine receptor binding is initially (as measured after 18 weeks treatment) decreased by HPTP treatment in the basal ganglia, frontal cortex (not significantly) and cerebellum but reversed to control values in the frontal cortex, as measured after 58 weeks treatment with HPTP. The binding to the basal ganglia and to a lesser degree the cerebellum is still affected after 58 weeks treatment with HPTP but indicates a tendency to return towards the control values. The results of the planar dynamic study with beta-CIT indicate a decrease in the beta-CIT binding to the dopamine transporters in the basal ganglia and to a lesser extent the cerebellum as measured by the time activity and percentage washout rate of the beta-CIT in the HPTP treated baboons. The effect of HPTP on the serotonin transporters appears to be minimal as observed from the results obtained from the frontal cortex. These results indicate that HPTP treatment influences both presynaptic and postsynaptic neurofunction in the dopaminergic neurones.

Animals↗
PubMed1996

Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study.

Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyrid ine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 99mTc-HMPAO (hexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the IBZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.

Animals↗
PubMed1996

Synthesis and selective monoamine oxidase B-inhibiting properties of 1-methyl-1,2,3,6-tetrahydropyrid-4-yl carbamate derivatives: potential prodrugs of (R)- and (S)-nordeprenyl.

The results of previous studies have established that the monoamine oxidase-catalyzed oxidation of 1-methyl-1,2,3,6-tetrahydropyridyl derivatives bearing heteroatom substituents at C-4 generates 2,3-dihydropyridinium intermediates that undergo spontaneous hydrolysis to release the C-4 substituent and form the amino enone 1-methyl-2,3-dihydro-4-pyridone. We have attempted to adapt this metabolic pathway to the preparation of amine-containing prodrugs that may target the central nervous system which is rich in monoamine oxidase A and B. In this paper we report the synthesis and the in vitro and in vivo metabolic fate of the tetrahydropyridyl carbamate derivatives which are designed to release (S)- and (R)-nordeprenyl. These carbamates are selective monoamine oxidase A substrates. An ex vivo assay has shown that the R-enantiomer is an effective and selective inhibitor of brain mitochondrial monoamine oxidase B.

Animals↗
PubMed1996

Assessment of structural requirements for the monoamine oxidase-B-catalyzed oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives related to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The monoamine oxidase B (MAO-B) substrate properties and distance measurements along the N1-C4 axis of 38 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives, including seven newly synthesized MPTP analogs, were used to define the maximum size that can be accommodated by the MAO-B active site. Only those compounds measuring less than 12 A displayed significant MAO-B substrate properties. The behavior of various 4-substituted-1-cyclopropyltetrahydropyridine analogs also is discussed in terms of this N1-C4 distance parameter in an effort to understand factors which contribute to their substrate vs inactivator properties. We conclude that this distance parameter will predict the majority of substrates vs nonsubstrates with this class of compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Effect of a pyridinium metabolite derived from haloperidol on the activities of striatal tyrosine hydroxylase in freely moving rats.

The effects of a pyridinium metabolite (HPP+) derived from haloperidol (HP) on in vivo tyrosine hydroxylation was evaluated in freely moving rats. As an index of the in vivo activity of tyrosine hydroxylase (TH), the rat striatum was perfused with NSD-1015, and extracellular 3,4-dihydroxyphenylalanine (DOPA) levels were measured. HPP+ (1 mM) gradually reduced tyrosine hydroxylation to 30% of the basal level, although the effect was less potent than 1-methyl-4-phenylpyridinium ion (MPP+). On the contrary, HPP+ at a 0.1 mM dose decreased in 5-hydroxyindoleacetic acid (5-HIAA) level, but did not affect dopamine metabolites. The present study revealed that HPP+ irreversible inhibited in vivo tyrosine hydroxylation by the same manner of MPP+. However, the neurotoxic effects of HPP+ in vivo would be selective for serotonergic over dopaminergic neurons, which distinguishes the toxic profile of this compound compared to that of MPP+.

1-Methyl-4-phenylpyridinium↗
PubMed1996

Deuterium isotope effect studies on the MAO-B catalyzed oxidation of 4-benzyl-1-cyclopropyl-1,2,3,6-tetrahydropyridine.

Previous studies have established that 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is an efficient time- and concentration-dependent inhibitor of the flavin-containing enzyme monoamine oxidase B (MAO-B). This behavior is consistent with a proposed mechanism-based inactivation pathway which proceeds via an initial single electron transfer step to generate an unstable cyclopropylaminyl radical cation intermediate that alkylates an active site functionality via the ring opened primary carbon centered radical. More recently we have found that, in addition to being an inhibitor, the corresponding 1-cyclopropyl-4-benzyl-1,2,3,6-tetrahydropyridine species is an excellent MAO-B substrate, behavior which may not be consistent with the obligatory formation of a cyclopropylaminyl radical cation intermediate. In an attempt to gain further insight into the mechanism associated with the MAO catalyzed oxidation of 1,4-disubstituted tetrahydropyridines, we have undertaken deuterium isotope effect studies on the substrate and inhibitor properties of this 4-benzyl-1-cyclopropyltetrahydropyridine derivative. A normal isotope effect was observed on kcat/KM. Although the good substrate properties of this compound prevented an accurate estimate of k(inact) and K1, we did observe a very modest inverse isotope effect on the rate of inactivation of 0.1 microM MAO-B by 500 microM inactivator. The results are discussed in terms of possible mechanisms for the MAO-B catalyzed oxidation of 1,4-disubstituted 1,2,3,6-tetrahydropyridines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Biotransformation of the MPTP analog trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetra- hydropyridine to a fluorescent pyridinium metabolite by intact neuroblastoma cells.

The possibility of imaging monoamine oxidase (MAO) containing neurons through the MAO-mediated conversion of the nonfluorescent tetrahydropyridine compound trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydro pyridine (t-THP) to the corresponding fluorescent trans-1-methyl-4-[4-dimethylaminophenylethenyl]pyridinium species (t-P+) was examined with the aid of human neuroblastoma cells (SH-SY5Y). Fluorescence microscopy and fluorescence measurements established the intracellular formation of a fluorescent species with maximal excitation/emission wavelengths of 485/620 and 530/620 nm corresponding to the fluorescence characteristics of synthetic t-P+. An independent assay confirmed the presence of both MAO-A and MAO-B in these cells. As expected, the development of the fluorescence was inhibited by both clorgyline (an MAO-A inhibitor) and deprenyl (an MAO-B inhibitor). Cytotoxic effects, as determined by trypan blue dye exclusion for viability and by the MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay for mitochondrial integrity, were not observed in cells incubated with concentrations of t-THP as high as 10(-3) M for 4 hr. The results from these studies with a neuronal cell line of human origin suggest: (1) that SH-SY5Y cells metabolize and, therefore, can be used for study of tetrahydropyridine compounds in vitro, and (2) that t-THP may be a useful agent to monitor neurodegenerative processes in MAO-rich neurons, including the dopaminergic nigrostriatal neurons that are damaged by the parkinsonian-inducing tetrahydropyrridine MPTP. The potential advantage of using t-THP over related imaging techniques is the possibility of assessing neuronal function by an in vivo processing of the reporter molecule rather than by postmortem immunofluorescent or formaldehyde-based procedures.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Dopamine receptor binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)- 4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP), an intermediate metabolite of haloperidol.

The neuroleptic agent haloperidol (HP) is biotransformed to metabolites such as 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP) and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium (HPP+). In this study, radioligand binding studies were performed using [3H]SCH23390 as a dopamine D1 receptor ligand and [3H]spiperone as a D2 ligand. Ki values for D1 receptors were 35.8 microM and 54.9 microM for HP and HPTP, respectively. Corresponding values for D2 receptors were 39.1 nM and 329.8 nM. These results indicate similar low affinities in the micromolar range for both HP and HPTP at the dopamine D1 receptor, a much higher affinity of both HP and HPTP for the D2 receptor than for the D1 receptor, and that HPTP binds to D2 receptors with a 9-fold lower affinity than HP. The data are consistent with observations in mice that HPTP is a much less potent acute neuroleptic agent than HP.

Animals↗
PubMed1996

Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridinium species in the baboon.

The in vivo metabolic fate of haloperidol (HP) and its tetrahydropyridine analog HPTP have been examined in the baboon to investigate the formation of potentially neurotoxic pyridinium metabolites that have been observed previously in humans. Urine samples collected from baboons treated with HPTP were shown to contain, in addition to the parent drug, the corresponding reduced HPTP (RHPTP), generated by reduction of the butyrophenone carbonyl group. RHPTP was characterized by comparison with a synthetic standard using HPLC with electrochemical detection and HPLC/MS/MS. Another compound identified by LC/MS/MS was a glucuronide metabolite of RHPTP. The HP pyridinium (HPP+) and reduced pyridinium (RHPP+) metabolites were shown to be present in urine from both HP and HPTP treated baboons by HPLC using fluorescence detection. The urinary excretion profile of HPP+ and RHPP+ in both groups was essentially identical and, in contrast to that observed in rodents, closely paralleled the profile found in humans treated with HP. These data in the baboon suggest that the metabolic processes involved in the production of the pyridinium metabolites of HP are similar to those in humans. Furthermore, the HPTP-treated baboon may be an appropriate model in which to study the role of pyridinium metabolites in the induction of tardive dyskinesia.

Animals↗
PubMed1996

Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives.

The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selected N-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have led us to consider a mechanism for these cyclic tertiary allylamines which may not necessarily involve the aminyl radical cation as required by an initial single-electron transfer step. The studies summarized in this paper were undertaken to explore further the structural features that determine the MAO-B substrate and/or inactivator properties of various 1,4-disubstituted tetrahydropyridine derivatives. We report here the results of our studies on the synthesis and MAO-B catalyzed oxidation of 1-methyl- and 1-cyclopropyl-1,2,3,6-tetrahydropyridine derivatives bearing a variety of heteroaromatic groups at C-4. All of the N-cyclopropyltetrahydropyridine analogs were time and concentration dependent inhibitors of MAO-B while all of the N-methyltetrahydropyridine analogs and the N-cyclopropyl-4-(1-methyl-2-pyrryl)tetrahydropyridine analog were substrates. The substrate properties (Kcat/KM) covered a range of 6 to 1800 min-1 mM-1 while the range for the inactivator properties for which Kinact/KI values could be obtained was 0.1-1.0 min-1 mM-1. The partition ratios for the N-cyclopropyl analogs varied from 4 to 17 except for the 4-(1-methyl-2-pyrryl) analog, which had a partition ratio of 400. These results are discussed in terms of the putative allylic radical intermediate and in the context of the hydrogen atom transfer and single-electron transfer based mechanisms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP.

The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated i.p. with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.

Animals↗
PubMed1995

Studies on the monoamine oxidase (MAO)-catalyzed oxidation of phenyl-substituted 1-methyl-4-phenoxy-1,2,3,6-tetrahydropyridine derivatives: factors contributing to MAO-A and MAO-B selectivity.

The structural parameters responsible for the substrate and inhibitor selectivities of the monoamine oxidases (MAO) A and B remain poorly understood. This situation has improved somewhat with structure-activity studies that have been performed on nuclear-substituted pargyline derivatives and 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results of these studies suggest that the active site of MAO-A is sterically more accommodating than the active site of MAO-B. In the present work we have undertaken a more systematic structure-substrate activity analysis with the aid of a series of 4-phenoxytetrahydropyridine analogs substituted at the para, meta, and ortho positions of the phenyl ring with chloro, methoxy, methyl, nitro, and phenyl groups. All of the compounds proved to be good substrates for both MAO-A and MAO-B, and all were better MAO-A substrates than MAO-B substrates. The best defined structural parameter relating to selectivity again was the relatively better MAO-A substrate properties of tetrahydropyridine derivatives bearing bulky C-4 substituents. Attempts to identify stereoelectronic effects related to substrate properties and selectivity with this series of compounds were not successful. Although some structural correlates with substrate activity can be made, overall the present state of knowledge is inadequate to provide good descriptors of structural features that characterize MAO-A and MAO-B substrates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Safety of acid-suppressing drugs.

There is an extensive literature on the adverse effects of drugs that inhibit gastric acid secretion. This study presents a critical examination of interactions between antisecretory drugs and other compounds, the frequency of serious adverse effects relating to various body systems, the safety of antisecretory drugs in pregnancy, and longer-term safety data from postmarketing surveillance studies. While interactions with some other drugs, alcohol, and certain carcinogens are of potential concern, in practice clinically significant reactions appear to be rare if they occur at all. A small number of major side-effects have been documented, but they occur rarely, and postmarketing surveillance has not detected other longer-term sequelae. Safety of these drugs in pregnancy is not established, as data are so few. It is concluded that antisecretory agents, by comparison with most other classes of drugs, are remarkably well tolerated.

Female↗
PubMed1995

Stereoselectivity and isotope effects associated with cytochrome P450-catalyzed oxidation of (S)-nicotine. The possibility of initial hydrogen atom abstraction in the formation of the delta 1', 5-nicotinium ion.

The stereochemical course of cytochromes P450 [P4501A1, P4502B1, P4502B4, and P450101 (P450cam)] catalyzed alpha-carbon oxidations of the cis-(Z)- and trans-(E)-5'-d1 diastereomers of (S)-nicotine has been examined. All enzyme preparations led to the stereoselective abstraction of the 5'-hydrogen atom trans to the pyridine ring with P450101 and human liver microsomal preparations displaying the highest (90%) and P4502B1 the lowest (67%) degree of stereoselectivity. No isotope effect was detected for any of the enzyme-catalyzed reactions, although the existence of an intrinsic isotope effect was inferred by the observation of an intramolecular isotope effect of 2-2.6 observed for the N-demethylation of (S)-N'-dideuteromethylnornicotine. Evidence for P450101-catalyzed N'-oxidation was sought but could not be found at higher than trace levels. These results, together with those obtained by computational methods, are interpreted in terms of an alpha-carbon oxidative pathway involving hydrogen atom abstraction rather than single electron transfer as the initiating event in the P450-catalyzed oxidation of (S)-nicotine to its delta 1',5'-iminium ion metabolite.

Animals↗