Lipoxygenase-Mediated N-Demethylation of Imipramine and Related Tricyclic Antidepressants in the Presence of Hydrogen Peroxide

Hu, Jianan; Sajan, Mini P.; Kulkarni, Arun P.

doi:10.1080/109158199225404

Cited by 6 publications

(5 citation statements)

References 28 publications

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“…Thus, in theory, the intracellular accessibility of imipramine is expected to be much higher to LO than to P450, MFMO, or PGS. The reported LO-mediated extensive N-demethylation of imipramine [61] strongly supports this view. Although a demonstration of the presence of P450 in trace amounts, for example, may be of some academic interest, the efficiency of the enzyme, in a practical sense is far more important and should not be ignored.…”

Section: Importance Of Lo-mediated Xenobiotic Metabolismsupporting

confidence: 71%

“…Since LO activity occurs in the liver and brain [55,122], its involvement in imipramine oxidation can be suspected. Exploration of this hypothesis revealed that imipramine is an excellent substrate for N-dealkylation by SLO in the presence of H 2 O 2 [61]. Desipramine, the expected product of imipramine mono N-demethylation, was identified by HPLC.…”

Section: Dealkylationmentioning

confidence: 99%

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Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Kulkarni¹

2001

CMLS, Cell. Mol. Life Sci.

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Lipoxygenase, a member of the arachidonate cascade enzymes, dioxygenates polyenoic fatty acids to finally yield products with profound and distinct biological activity. This review summarizes the available evidence for another role played by lipoxygenases in the metabolism of endobiotics and xenobiotics. Although other mechanisms exist, a direct hydrogen abstraction by the enzyme and the peroxyl radical-dependent chemical oxidation appear to be central to the co-oxidase activity of lipoxygenases. Besides polyunsaturated fatty acids, H2O2, fatty acid hydroperoxides, and synthetic organic hydroperoxides support the lipoxygenase-catalyzed xenobiotic oxidation. The major reactions documented thus far include oxidation, epoxidation, hydroxylation, sulfoxidation, desulfuration, dearylation, and N-dealkylation. It is noteworthy that lipoxygenases are also capable of glutathione conjugation of certain xenobiotics. The enzyme system appears to be inducible following exposure to chemicals. Lipoxygenases are inhibited by a large number of chemicals, some of which also serve as co-substrates. Available data suggest that lipoxygenases contribute to in vivo metabolism of xenobiotics in mammals.

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Section: Importance Of Lo-mediated Xenobiotic Metabolismsupporting

confidence: 71%

Section: Dealkylationmentioning

confidence: 99%

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Kulkarni¹

2001

CMLS, Cell. Mol. Life Sci.

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“…In light of these observations, a hypothesis that LO may be involved was tested using SLO. The results indicated that imipramine is an excellent substrate and undergoes dealkylation at the rate of ~114 nmoles/min/mg SLO in the presence of H 2 O 2 [174]. Desipramine, the expected product of imipramine mono Ndemethylation, was identified by HPLC.…”

Section: Drugsmentioning

confidence: 98%

Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Kulkarni

2001

CPD

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Many developmental toxicants and teratogens require prior metabolism to reactive species or free radicals to exert toxicity. Thus the knowledge of conceptal biotransformation is absolutely critical in understanding toxicity of these chemicals. Due to extremely low content of cytochrome P450 in the embryo and other conceptal tissues, the research focus in recent years has steadily shifted toward enzymes capable of peroxidative oxidation of xenobiotics. At least three enzymes viz. lipoxygenase, peroxidase and prostaglandin synthase, each capable of peroxidative xenobiotic metabolism, occur in conceptal tissues of man and laboratory animals in biologically significant amounts. This review mainly summarizes the available information on the enzymatic bioactivation of teratogens and developmental toxicants belonging to diverse classes such as drugs, pesticides, environmental contaminants, industrial and other chemicals. Additionally, some discussion is devoted toward issues such as drug-drug interactions. The emerging new information on the peroxidative glutathione conjugate formation from xenobiotics is also presented. A critical need for gathering more information on this subject using different enzyme preparations from human conceptal tissues is stressed to avoid tragedies in the future.

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“…However, they too have been found to be able to undertake the metabolism of a variety of xenobiotic substrates. In various studies, lipoxygenase was shown to act upon several tricyclic drugs including amitryptiline, chlorpromazine, doxepin, imipramine, promazine and promethazine [87][88][89][90] in addition to oxyphenbutazone [91] and phenytoin [92]. Similarly, prostaglandin H-synthase catalysed the biotransformation of many xenobiotic compounds as well as the drugs, aminopyrine [93], diethylstilboestrol [94,95], oestradiol [96], phenylbutazone [97] and sulindac sulfide [98,99].…”

Section: Reflections On the Futurementioning

confidence: 99%

Foreign Compounds and Intermediary Metabolism: Sulfoxidation Bridges the Divide

Mitchell

Steventon²

2009

CDM

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It is widely appreciated that as a xenobiotic travels through an organism and interacts with the biochemical machinery of a living system, it most probably will undergo a number of metabolic alterations usually leading to a cluster of differing chemical species. Indeed, the modern 'metabonomic' approach, where earlier studied drug metabolism profiles have been reassessed, has indicated that there are normally many more previously unrecognised minor metabolites, and when all such biotransformation products are considered, then their total number is legion. It is now being recognised also that the same metabolic alteration of a substrate, especially a xenobiotic substrate, may be catalysed by more than one enzyme and that the previously sacrosanct notion of an enzyme's 'substrate specificity' may well be inverted to read a substrate's 'enzyme preference'. The following brief article attempts to highlight another aspect where our general acceptance of the 'status quo' needs to be reconsidered. The conventionally acknowledged division between the collection of enzymes that undertake intermediary metabolism and the group of enzymes responsible for xenobiotic metabolism may be becoming blurred. It may well be a prudent time to reassess the current dichotomous view. Overcoming inertia, with a realignment of ideas or alteration of perception, may permit new concepts to emerge leading to a more profound understanding and hopefully eventual benefits for mankind.

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Lipoxygenase-Mediated N-Demethylation of Imipramine and Related Tricyclic Antidepressants in the Presence of Hydrogen Peroxide

Cited by 6 publications

References 28 publications

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Role of Biotransformation in Conceptal Toxicity of Drugs and Other Chemicals

Foreign Compounds and Intermediary Metabolism: Sulfoxidation Bridges the Divide

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