Enhancement and Inhibition of Drug Metabolism

Anders, M. W.

doi:10.1146/annurev.pa.11.040171.000345

Cited by 141 publications

(29 citation statements)

References 41 publications

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“…of 5 mice, P<0.001, Student's t-test). The difference in DOI-induced head twitch response between the two groups was also observed in mice pretreated with proadifen, an inhibitor of the drug-metabolizing enzyme (9,10): the head twitch responses induced by DOI (5 mg /kg, i.p.) (counts /10 min) in mice pretreated with proadifen (50 mg /kg, i.p., 30 min before DOI) were 23 ± 1 (grouped mice) and 33 ± 1 (isolated mice) (means ± S.E.M.…”

Section: -Hydroxytryptamine (5-ht)mentioning

confidence: 79%

Modulation by 5-HT2A Receptors of Aggressive Behavior in Isolated Mice

Sakaue

Ago

Sowa

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-The present study examines whether isolation-rearing affects sensitivity of 5-hydroxytryptamine (5-HT)2A receptors and the functional interaction between 5-HT1A and 5-HT2A receptors in mice. The 5-HT2A-receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch response was significantly greater in isolated mice than in grouped mice. DOI increased isolation-induced aggressive behavior, and the 5-HT 2A -receptor antagonist ritanserin decreased it. The 5-HT 1A -receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) inhibited the DOI-enhanced aggressive behavior. MKC-242 inhibited DOI-induced head twitch response. These findings suggest that 5-HT 2A receptors play a role in aggressive behavior in isolated mice and imply that the antiaggressive effect of MKC-242 may be mediated partly by the inhibition of 5-HT 2A -receptor function.Keywords: 5-Hydroxytryptamine (5-HT)2A receptor, Aggression, 5-HT1A receptor 5-Hydroxytryptamine (5-HT) 1A -receptor agonists, which have an anxiolytic-like effect, reduce aggressive behavior in isolated male mice (1 -4), but the exact mechanism remains unknown. We have shown that cortical dopaminergic activity is enhanced and the sensitivity of 5-HT1A receptors that stimulate cortical dopamine release is reduced in isolated mice (5). In addition, we showed that the antiaggressive effect of the selective 5-HT1A-receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) (6) was antagonized by flumazenil, a benzodiazepine-receptor antagonist (7). These findings suggest that dopaminergic neurons play a role in mediating the aggressive behaviors in isolated mice and that C-aminobutyric acid neurons are involved in the antiaggressive effect of MKC-242. By contrast, previous studies have shown that the downregulation of 5-HT2A receptors is involved in the antidepressant-like and anxiolytic-like effects of 5-HT1A-receptor agonists (8). However, it is not known whether 5-HT2A receptors are involved in isolationinduced aggressive behavior. In the present study, we examine the possible involvement of the 5-HT2A receptors in isolation-induced aggressive behavior and the effect of MKC-242 on 5-HT 2A -receptor-mediated response in mice.Male ddY mice (4-week-old) were either housed in groups of 5 -6 /cage (24´17´12 cm) or isolated in the same size cage for more than 6 weeks before experiments under controlled environmental conditions (22 ± 1°C; 12 -12 light-dark cycle, lights on at 0800, food and water ad libitum). Procedures involving animals and their care were conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals approved by The Japanese Pharmacological Society. The isolated mice were prescreened for aggressive behavior once a day for one or two days prior to the experiment. An intruder mouse was introduced into the isolated mouse's home cage for 3 min, and the isolated mice exhibiting bite marks were used for the dru...

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Section: -Hydroxytryptamine (5-ht)mentioning

confidence: 79%

Modulation by 5-HT2A Receptors of Aggressive Behavior in Isolated Mice

Sakaue

Ago

Sowa

et al. 2002

Japanese Journal of Pharmacology

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“…It is well known that MAO inhibitors inhibit microsomal enzyme systems in the liver cells and thus reduce drug metabolism (Fouts & Brodie, 1956;Laroche & Brodie, 1960;Kato, Chiesara & Vasanelli, 1964). The metabolism of ethylmorphine (Anders & Mannering, 1966) and pethidine (Clark, 1967) is inhibited in vitro by iproniazid and by phenelzine respectively. Nevertheless, there is a considerable body of evidence arguing against the hypothesis that in vivo the analgesic/MAO inhiibitor interaction is due to this mechanism.…”

Section: Mao Inhibitors and Analgesics Discussionmentioning

confidence: 99%

The interaction between monoamine oxidase inhibitors and narcotic analgesics in mice

Rogers

Thornton

1969

British J Pharmacology

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1. The administration of either iproniazid or tranylcypromine to mice potentiates the acute toxicity of pethidine, morphine, pentazocine and phenazocine. 2. Blood levels of pentazocine in mice pretreated with tranylcypromine do not differ from the levels in animals not receiving the monoamine oxidase (MAO) inhibitor. 3. There is no correlation ibetween changes in brain and liver MAO activity and the increased pethidine toxicity. 4. A comparison is made between the change in pethidine toxicity and the changes in the concentration of cerebral noradrenaline, dopamine and 5-hydroxytryptamine following the injection of tranylcypromine. 5. It is concluded that the increased toxicity of potent analgesics in combination with MAO inhibitors is not due to a decelerated meta(bolism of the analgesic drug, but is related to an increases concentration of cerebral 5-hydroxytryptamine. A critical level of this monoamine, in the brain, may be necessary before the drug interaction will take place.Monoamine oxidase (MAO) inhibitors are known to potentiate the effects of a wide variety of pharmacological agents, and severe toxic reactions have been observed when certain drugs have been given to patients receiving MAO inhilbitors for the treatment of depressive states. This group of drug interactions has been the subject of reviews (by Goldiberg (1964) and Sjoquist (1965). The majority of the .adverse reactions are caused by agents which, like MAO inhilbitors, exert an effect on monoaminergic neurotransmission. Some drugs, however, interact with MAO inhibitors by mechanisms which remain to be fully elucidated. The narcotic analgesics, and in particular pethidine, provide an example.The adverse reaction to pethidine is said to be due to a decelerated breakdown 'of the analgesic drug, since MAO inhibitors are known to exert non-specific effects on detoxifying enzyme systems in the liver. A decelerated breakdown of pethidine would explain an exaggeration of the normal response to this drug, namely hypotension and respiratory depression, but it does not explain other reported effects such as hypertension and hyperpyrexia, effects which occur soon after the administration of pethidine to patients receiving MAO inhilbitors (Rogers, Jepson, Kilpatrick & Thornton, unpublished). Furthermore, although the toxicity of other potent

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“…On the other hand, heat treated-cytochrome b5 did not affect the activity of aniline hydroxylation in the presence or absence of acetone (none, 0.42 nmole/nmole P-450/min; heat treated cytochrome b5 alone, 0.40 nmole/nmole P 450/min; acetone alone, 0.64 nmole/nmole P-450/min; acetone and heat treated cytochrome b5, 0.61 nmole/nmole P-450/ min; acetone and untreated-cytochrome b5, 1.07 nmole/nmole P-450/min). The effect of cytochrome b5 on aniline hydroxylation was also observed when 2,2'-bipyridine was added to the system in place of acetone ( (10, 18) that the synergistic effect of NADH on NADPH dependent microsomal aniline hydroxylation was observed in the presence of acetone or 2,2'-bipyridine which is known to be enhancing agents of aniline hydroxylation (19). The present study shows that cyto chrome b5 stimulates NADPH-dependent aniline hydroxylation in the presence of acetone or 2,2'-bipyridine.…”

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confidence: 91%