Substrate specificity of guinea pig liver flavin-containing monooxygenase for morphine, tropane and strychnos alkaloids

Yuno, Koichiro; Yamada, Hideyuki; Oguri, Kazuta; Yoshimura, Hidetoshi

doi:10.1016/0006-2952(90)90737-6

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…FAD-containing monooxygenases are involved both in the first (Kloss et al 1983 a) and in the second step of oxidative metabolism (Kloss et al 1982a). Norcocaine is an excellent substrate (apparent Km 15 ~M) in mouse hepatic microsomes (Kloss et al 1982a), whereas cocaine is a poor substrate for FAD-containing monooxygenases; the apparent Km in a purified guinea pig enzyme system was 2.8 mM (Yuno et al 1990). …”

Section: Role Of Cytochrome P-450 and Fad-containing Monooxygenasesmentioning

confidence: 97%

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Boelsterli

Göldlin

1991

Arch Toxicol

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Cocaine is an intrinsic hepatotoxin in laboratory animals, and there is growing evidence that high doses of cocaine can precipitate hepatic necrosis in humans. The rodent model of cocaine hepatotoxicity is commensurate with the concept that a multistep mainly cytochrome P-450 dependent N-oxidative pathway is responsible for the expression of hepatocellular injury. Among the possible biomechanisms by which cocaine exerts its cytotoxic effects, direct oxidative damage by reactive oxygen species generated by redox cycling during the metabolic cascade seems most important. The role of the ensuing lipid peroxidation and protein thiol oxidation is less clear. Similarly, the functional role of irreversible (covalent) binding of a not yet defined electrophilic cocaine intermediate to hepatocellular proteins remains enigmatic so long as the critical molecular targets have not been identified. Finally, glutathione plays a pivotal protective role against cocaine-induced hepatic injury. Interactions with ethanol or inducers of the expression of the cytochrome P-450IIB subfamily can potentiate cocaine hepatotoxicity. Thus, the net amount of the ultimate reactive species seems to determine the severity of the hepatic lesions and to be responsible for the marked interspecies, interstrain, and sex differences. Recent advances in culture techniques of hepatocytes and precision-cut liver slices from various species including man have made it possible to correlate cocaine biotransformation with cytotoxicity and to selectively study the putative cellular mechanisms. Clearly, more studies are necessary to further illuminate our understanding of the role of the biochemical and molecular events precipitating hepatic necrosis during cocaine-mediated hepatotoxicity.

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Section: Role Of Cytochrome P-450 and Fad-containing Monooxygenasesmentioning

confidence: 97%

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Boelsterli

Göldlin

1991

Arch Toxicol

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“…Nevertheless, the suggestion that FMO evolved to oxidize and detoxicate nucleophilic heteroatom-containing chemicals or their metabolites present in many plants probably also applies to the adult human FMOs as well (2). As Ziegler has stated before, based on work done mainly with animal liver FMOl, the tissue distribution of FMO and the recalcitrance of FMO to inactivation by many chemicals present in plants that otherwise readily inactivate cytochromes P-450 and other hemoproteins suggest that the broad multisubstrate FMO is intended to prevent the untoward effects of bioactivation of chemicals by cytochromes P-450 ( compounds to less biologically toxic materials (138,139).…”

Section: Role Of Fmo In Human Chemical and Drug Metabolismmentioning

confidence: 99%

Structural and Catalytic Properties of the Mammalian Flavin-Containing Monooxygenase

Cashman¹

1995

Chem. Res. Toxicol.

205

144

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“…The study of the metabo lism of 3 (p chlorophenyl)pyrrolidine (13), which is the prodrug of the myorelaxant Baclofen, showed that its transformation follows two pathways (Scheme 12) 9 to give Baclofen (14) and Baclofen Lactam (15) (path A) or α Baclofen (16) and α Baclofen Lactam (17) (path B). The path A is preferred over the cytochrome P450 catalyzed oxidation (path B) due apparently to steric factors.…”

Section: Metabolic Transformations Of Heterocyclesmentioning

confidence: 99%

“…13 The phase II metabolism involves also the conjugation with fatty acids typical of various heterocycles, including O heterocyclic compounds. The process is exemplified by the cannabinol derivative (56), 2,4 which is an active ingre dient of the cannabis resin (the narcotic substances mari juana and hashish from Indian hemp causing narcotic ad diction).…”

Section: Scheme 24mentioning

confidence: 99%

Biotransformations of drugs belonging to nitrogen heterocycles

Граник

2010

Russ Chem Bull

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The present review covers general aspects related to the metabolism of organic compounds, primarily, of biologically active azaheterocycles used as drugs. Compounds of this type occupy a dominant place among known drugs. Data on the main chemical processes determining the pathways of principal biotransformations, such as redox reactions, hydrolysis, alkylation, acy lation, various conjugations, isomerizations, and condensations, are summarized. The metabo lisms of heterocycles is considered based on the ring size of the substrate.

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Substrate specificity of guinea pig liver flavin-containing monooxygenase for morphine, tropane and strychnos alkaloids

Cited by 6 publications

References 16 publications

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Structural and Catalytic Properties of the Mammalian Flavin-Containing Monooxygenase

Biotransformations of drugs belonging to nitrogen heterocycles

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