Phenobarbital-like inducers

Poland A, Mak I, Glover E, et al. 1,4-/Rv[2-(3,5-dichloropyridyloxy)]benzene, a potent phenobarbital-like inducer of microsomal monooxygenase activity. Mol Pharmacol 1980 18 571-80. 

Schuetz, E.G., S.A. Wrighton, S.H. Safe and P.S. Guzelian. Regulation of cytochrome P-450p by phenobarbital and phenobarbital-like inducers in adult rat hepatocytes in primary monolayer culture and in vivo. Biochemistry 25 1124-1133, 1986. 

Inducer AEDs. Antiepileptic drugs that have phenobarbital-like inducer effects... 

Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that induce certain cytochrome P-450 isozymes (Nastainczyk et al. 1982a Thompson et al. 1984). Exposure to food material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachloroethane metabolism and thus influence its toxicity. 

Table 3.6 Examples of phenobarbital-like enzyme inducers ...

There are basically three types of cytochrome P450 inducers (1) phenobarbital-like (the major class) (2) methylcholanthrene-like (which actually increases a P448 isozyme) and (3) anabolic steroids. The former two have been the most frequently studied. Research over the past 40-50 years indicates that their mechanism of action involves genetic interaction, possibly via derepression of a repressor gene, and the subsequent synthesis of mRNA for the specific enzyme proteins. Examples of phenobarbital-like enzyme inducers, the most common, are shown in Table 3.6. 

The above sequence mimics the proposed biosynthesis of Ervatamia alkaloids and in this context Thai and Mansuy (190) set out to determine whether an enzyme preparation would be able to promote the same transformation. By incubation of dregamine hydrochloride with a suspension of liver microsomes from a rat pretreated with phenobarbital (as a good inducer of P-450 cytochromes) in the presence of NADPH and 02, 20-epiervatamine (45) was formed together with the major metabolite Nl -demethyldregamine. It is well known that microsomal reaction on tertiary amines results in Af-oxide formation or N-deal-kylation. Thus it is likely that 45 was derived either from a rearrangement of dregamine JV4-oxide, catalyzed by the iron cytochrome P-450 or from one-electron oxidation of 30. 

Barbiturate drugs like pentobarbital (Nembutal ), secobarbital (Seconal ), amobarbital (Amytal ), and phenobarbital are extremely potent sedatives that induce sleep, mostly non-REM sleep. However, barbiturates actually decrease the amount of REM sleep a person gets. Thus, if a person took a barbiturate as a sleep aid nightly for a week, the total amount of REM sleep would be significantly less than if he or she was not taking the drug. Then, when the person stopped taking the barbiturate, he or she would experience a severe REM... 

Sedative-hypnotic drugs and anxiolytic drugs are CNS depressants that are used medically to reduce anxiety and/or induce sleep. They may also be used as anticonvulsants. Phenobarbital, for example, is often the maintenance drug of choice for seizure-prone individuals. In general, the sedative-hypnotic family of drugs includes alcohol, barbiturates, benzodiazepines, and such barbiturate-like drugs as chloral hydrate, glutethi-mide, meprobamate, and methaqualone. 

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