Role of the Lung in Accumulation and Metabolism of Xenobiotic Compounds — Implications for Chemically Induced Toxicity

Foth, Heidi

doi:10.3109/10408449509021612

Cited by 56 publications

(14 citation statements)

References 300 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, as FMO5 has a very restricted substrate range that is quite distinct from that of any other FMO (18,60), it would be unable to substitute for FMO2. The lung plays a significant role in the metabolism of certain foreign compounds (61,62). Although the pharmacological or toxicological significance of the absence of FMO2 in human lung remains to be established, it is clear that caution should be exercised when extrapolating pulmonary drug metabolism data from experimental animals to man if an FMO-mediated metabolic pathway is suspected.…”

Section: The Nonsense Mutation In the Human Fmo2 Gene Occurred After mentioning

confidence: 99%

The Flavin-containing Monooxygenase 2 Gene (FMO2) of Humans, but Not of Other Primates, Encodes a Truncated, Nonfunctional Protein

Dolphin¹,

Beckett²,

Janmohamed³

et al. 1998

Journal of Biological Chemistry

125

123

View full text Add to dashboard Cite

Flavin-containing monooxygenases (FMOs) are NADPH-dependent flavoenzymes that catalyze the oxidation of heteroatom centers in numerous drugs and xenobiotics. FMO2, or "pulmonary" FMO, one of five forms of the enzyme identified in mammals, is expressed predominantly in lung and differs from other FMOs in that it can catalyze the N-oxidation of certain primary alkylamines. We describe here the isolation and characterization of cDNAs for human FMO2. Analysis of the sequence of the cDNAs and of a section of the corresponding gene revealed that the major FMO2 allele of humans encodes a polypeptide that, compared with the orthologous protein of other mammals, lacks 64 amino acid residues from its C terminus. Heterologous expression of the cDNA revealed that the truncated polypeptide was catalytically inactive. The nonsense mutation that gave rise to the truncated polypeptide, a C 3 T transition in codon 472, is not present in the FMO2 gene of closely related primates, including gorilla and chimpanzee, and must therefore have arisen in the human lineage after the divergence of the Homo and Pan clades. Possible mechanisms for the fixation of the mutation in the human population and the potential significance of the loss of functional FMO2 in humans are discussed.

show abstract

Section: The Nonsense Mutation In the Human Fmo2 Gene Occurred After mentioning

confidence: 99%

The Flavin-containing Monooxygenase 2 Gene (FMO2) of Humans, but Not of Other Primates, Encodes a Truncated, Nonfunctional Protein

Dolphin¹,

Beckett²,

Janmohamed³

et al. 1998

Journal of Biological Chemistry

125

123

View full text Add to dashboard Cite

show abstract

“…Whereas metabolic activation of NNK has been demonstrated in lung tissue explants, isolated cells and microsomes from a variety of species, including hamster, mouse, rat and man (Tjälve 1991, for review), only little is known about NNK metabolism in the intact lung where the structural features of the organ are taken into account (Foth 1995;). According to Rivenson et al (1991), NNK may be considered a 'blood-borne' carcinogen because it is transported by the blood stream via the vascular network to the individual organs and tissues like the liver and nasal cavity.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Schrader

Hirsch‐Ernst

Richter

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects NNK requires metabolic activation which is supposed to take place via alpha-hydroxylation, whereas N-oxidation is suggested to be a detoxification pathway. The differences in the organ specific metabolism of NNK may be crucial for the organotropy in NNK-induced carcinogenesis. Therefore, metabolism of NNK was investigated in the target organ lung and in liver of Fischer 344 (F344) rats using the model of isolated perfused organs. High activity to metabolize 35 nM [5-3H]NNK was observed in both perfused organs. NNK was eliminated by liver substantially faster (clearance 6.9 +/- 1.6 ml/min, half-life 14.6 +/- 1.2 min) than by lung (clearance 2.1 +/- 0.5 ml/min, half-life 47.9 +/- 7.4 min). When the clearance is calculated for a gram of organ or for metabolically active cell forms, the risk with respect to carcinogenic mechanisms was higher in lung than in liver. The metabolism of NNK in liver yielded the two products of NNK alpha-hydroxylation, the 4-oxo-4-(3-pyridyl)-butyric acid (keto acid) and 4-hydroxy-4-(3-pyridyl)-butyric acid (hydroxy acid). In lung, the major metabolite of NNK was 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide). Substantial amounts of metabolites formed from methyl hydroxylation of NNK, which is one of the two possible pathways of alpha-hydroxylation, were detected in lung but not in liver perfusion. Formation of these metabolites (4-oxo-4-(3-pyridyl)-butanol (keto alcohol), and 4-hydroxy-4-(3-pyridyl)-butanol (diol) can give rise to pyridyloxobutylating of DNA. When isolated rat livers were perfused with 150 microM NNK, equal to a dosage which is sufficient to induce liver tumors in rat, glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased when compared to the concentration of 35 nM NNK. Nevertheless, the main part of NNK was also transformed via alpha-hydroxylation for this high concentration of NNK.

show abstract

“…Accordingly, it has been suggested that intracellular reduction of nifurtimox explains both its trypanocide action and its toxicity in mammals (Núñez-Vergara et al, 1997;Docampo, 1990). A similar hypothesis has been proposed to explain the toxicity of nitrofurantoin, an antibacterial drug (Hoener et al, 1989;Foth, 1995;Amit et al, 2002). However, the −NO 2 · − intermediate may continue in the reductive pathway leading to the nitroso-derivative (Wardman, 1985;Docampo et al, 1988;Orna and Mason, 1989) with no apparent toxicological consequences.…”

Section: Introductionmentioning

confidence: 97%

Liver microsomal biotransformation of nitro‐aryl drugs: mechanism for potential oxidative stress induction

Letelier

Izquierdo

Godoy

et al. 2004

J of Applied Toxicology

View full text Add to dashboard Cite

Toxic effects of several nitro-aryl drugs are attributed to the nitro-reduction that may be suffered in vivo, a reaction that may be catalysed by different reductases. One of these enzymes is NADPH-cytochrome P450 reductase, which belongs to the cytochrome P450 oxidative system mainly localized in the endoplasmic reticulum of the hepatic cell. This system is responsible for the biotransformation of oxidative lipophilic compounds, so that oxidative and reductive metabolic pathways of lipophilic nitro-aryl drugs can take place simultaneously. Because of the affinity of nitro-aryl drugs (xenobiotics) for the endoplasmic reticulum, we propose this subcellular organelle as a good biological system for investigating the toxicity induced by the biotransformation of these or another compounds. In this work we used rat liver microsomes to assess the oxidative stress induced by nitro-aryl drug biotransformation. Incubation of microsomes of rat liver with nifurtimox and nitrofurantoin in the presence of NADPH induced lipoperoxidation, UDP-glucuronyltransferase activation and an increase in the basal microsomal oxygen consumption. Nitro-aryl-1,4-dihydropyridines did not elicit these prooxidant effects; furthermore, they inhibited lipoperoxidation and oxygen consumption induced by Fe3+/ascorbate. Nifurtimox and nitrofurantoin modified the maximum absorption of cytochrome P450 oxidase and inhibited p-nitroanisole O-demethylation, an oxidative reaction catalysed by the cytochrome P450 system, signifying that oxidation may proceed in a similar way to that described for nitro-aryl-1,4-dihydropyridines. Thus the balance between lipophilic nitro-aryl drug oxidation and reduction may be involved in the potential oxidative stress induced by biotransformation.

show abstract

Role of the Lung in Accumulation and Metabolism of Xenobiotic Compounds — Implications for Chemically Induced Toxicity

Cited by 56 publications

References 300 publications

The Flavin-containing Monooxygenase 2 Gene (FMO2) of Humans, but Not of Other Primates, Encodes a Truncated, Nonfunctional Protein

The Flavin-containing Monooxygenase 2 Gene (FMO2) of Humans, but Not of Other Primates, Encodes a Truncated, Nonfunctional Protein

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in isolated rat lung and liver

Liver microsomal biotransformation of nitro‐aryl drugs: mechanism for potential oxidative stress induction

Contact Info

Product

Resources

About