Induction of cytochrome P-450 by alcohols and 4-substituted pyrazoles

Sinclair, Jacqueline F.; Cornell, Neal W.; Zaitlin, Linda M.; Hansch, Corwin

doi:10.1016/0006-2952(86)90370-9

Cited by 25 publications

(11 citation statements)

References 13 publications

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“…Cocultures were not any more effective than the regular cultures in the inducibility or maintenance of P-450IIE1 (data not shown). A variety of alcohols have been shown to be capable of inducing P-450 from both the IIB and the IIE sub-families in cultured check embryo hepatocytes (69,70). We are not aware of any study reporting induction of P-450IIE1 in a mammalian culture model.…”

Section: Discussionmentioning

confidence: 98%

Rapid decrease of cytochrome P-450IIE1 in primary hepatocyte culture and its maintenance by added 4-methylpyrazole

Clejan

Potter

et al. 1990

Hepatology

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Studies were conducted to evaluate the possible induction or the maintenance of cytochrome P-450IIE1 in primary hepatocyte cultures by the inducing agent 4-methylpyrazole. Hepatocytes were isolated from control (noninduced) rats and from rats treated in vivo with either pyrazole or 4-methylpyrazole to induce P-450IIE1. The content of P-450IIE1 was determined by Western blots with antipyrazole P-450 IgG, and catalytic activity was assessed by assays of dimethylnitrosamine demethylase activity. The treatment with 4-methylpyrazole in vivo increased the content of P-450IIE1 and dimethylnitrosamine demethylase activity sevenfold and fourfold, respectively. In cultures prepared from noninduced hepatocytes, P-450IIE1 levels fell to values of 76%, 65%, 31% and 1% of freshly isolated hepatocytes after 1, 3, 6 and 9 days in culture. A similar decrease in dimethylnitrosamine demethylase was observed during this time. In cultures prepared from induced hepatocytes, the decline in P-450IIE1 was more rapid as levels fell to 77%, 31%, 3% and 3% of initial values after 1, 3, 6 and 9 days in culture. Again, the fall in dimethylnitrosamine demethylase activity paralleled the decline in content of P-450IIE1 and was more rapid with the induced hepatocytes. With cultures prepared from noninduced or induced hepatocytes, the addition of 4-methylpyrazole in vitro did not increase the content of P-450IIE1 or the activity of dimethylnitrosamine demethylase over the initial values. However, 4-methylpyrazole appeared to stabilize the P-450IIE1 and to decrease its rate of decline in culture. In noninduced cultures, the percent remaining content of P-450IIE1 after 6 days was 31% in the absence of and 52% in the presence of 5 mol/L 4-methylpyrazole. In cultures from 4-methylpyrazole-induced hepatocytes, the percent remaining P-450IIE1 after 3 days was 31% in the absence of inducer and 59% with 4-methylpyrazole added in vitro. Similarly 4-methylpyrazole helped to prevent the rapid decline of dimethylnitrosamine demethylase activity in induced and noninduced cultures. Viability of the induced and noninduced cultures in the absence or presence of added 4-methylpyrazole was similar. Levels of mRNA for P-450IIE1 were similar for livers from control rats and from rats treated in vivo with 4-methylpyrazole. The mRNA levels rapidly declined in induced and noninduced cultures, and this decline, unlike the fall in P-450IIE1 or dimethylnitrosamine demethylase activity, could not be prevented by the addition of 4-methylpyrazole in vitro to the cultures.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionmentioning

confidence: 98%

Rapid decrease of cytochrome P-450IIE1 in primary hepatocyte culture and its maintenance by added 4-methylpyrazole

Clejan

Potter

et al. 1990

Hepatology

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“…(1335) CYPs can be induced by various chemicals and this ability, in limited series of compounds, increases with lipophilicity. (1336) The studies of CYP interactions with model bilayers 355,1337 are important for understanding the CYP mechanism and the prediction of CYP metabolism.…”

Section: Individual Steps Vs Propertiesmentioning

confidence: 99%

Modeling Kinetics of Subcellular Disposition of Chemicals

Baláž

2009

Chem. Rev.

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“…Information regarding the period of maximal PB induction (i.e. 11–12 days of incubation) are useful in in vivo quantitative structure‐activity relationship investigations, to substantiate a direct correlation between inducing ability and hydrophobicity of chemicals found in vitro (Sinclair et al , 1986; Hansch et al , 1990). It would be possible to determine exactly the day at which the induction of a particular CYP is highest to examine a series of chemicals metabolized by such an isoform.…”

Section: Discussionmentioning

confidence: 99%

Development of basal and induced testosterone hydroxylase activity in the chicken embryo in ovo

Paolini

Pozzetti

Sapone

et al. 1997

British J Pharmacology

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Medical Branch at Galveston, TX, U.S.A.1 The sensitivity of the developing embryo to xenobiotics is highly dependent on the expression of metabolizing enzymes including cytochromes P450 (CYP). In the present study, therefore, the ontogeny of the CYP-dependent system in the chick was investigated with testosterone hydroxylase activity as a marker of CYP expression. 2 Chicken embryo livers were assayed for basal and phenobarbitone (PB)-induced regio-and stereoselective testosterone hydroxylase activity, from the ®rst appearance of the liver as a discrete organ at 5 days of incubation through day 10 posthatching. In addition, whole embryo preparations were assayed at 3 and 4 days of incubation. 3 Whereas testosterone 16b-hydroxylase and androst-4-ene-3,17-dione-linked activities were expressed during all stages of embryonic development, testosterone 6a-, 6b-, 7a-and 16a-hydroxylase activities were observed only in basal embryos from 8 days of incubation. Furthermore, testosterone 2a-and 2b-hydroxylase activities were detected exclusively from 10 days of incubation onward. All activities increased steadily throughout development as did the responsiveness of the embryonic liver to PB induction. 4 A typical pattern of development with a higher activity from 10 to 14 days of incubation (testosterone 16a-, 7a-, 6a-and 2b-hydroxylase activities; up to 4.1+0.3 pmol mg 71 protein min 71 at 13 days of incubation for testosterone 7a-hydroxylase) or shifted to 14 to 18 days of incubation (testosterone 6b-, 2a-and 16b-hydroxylase activities: up to 56.6+1.4 pmol mg 71 protein min 71 at 16 days of incubation for testosterone 6b-hydroxylase) was observed. There was a tendency towards an increased activity for all activities around hatching, speci®cally from 19 days of incubation to 4 days posthatching (up to 1,759.3+179.4 pmol mg 71 protein min 71 at 1 day posthatching for androst-4-ene-3,17-dione-linked activity). 5 The highest level of PB-induced enzyme activity was observed for testosterone 2a-hydroxylase activity (95.14+7.35 and 660.19+45.27 pmol mg 71 protein min 71 ) at 12 days of incubation and day 3 posthatching, respectively. Except for testosterone 2a-and 2b-hydroxylase activities at 3 to 4 days of incubation, all metabolites were detectable during the ®rst period of organogenesis in the presence of PB. 6 The use of highly speci®c substrates, studies on the immunoinhibition of metabolism by polyclonal antibodies raised against highly puri®ed rat CYPs, and the use of selective inhibitors seemed to reveal a wide pleiotropic response with the posssible presence in liver of PB-treated chickens of CYP1A together with CYP2H1/H2, CYP2E and CYP3A.

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Induction of cytochrome P-450 by alcohols and 4-substituted pyrazoles

Cited by 25 publications

References 13 publications

Rapid decrease of cytochrome P-450IIE1 in primary hepatocyte culture and its maintenance by added 4-methylpyrazole

Rapid decrease of cytochrome P-450IIE1 in primary hepatocyte culture and its maintenance by added 4-methylpyrazole

Modeling Kinetics of Subcellular Disposition of Chemicals

Development of basal and induced testosterone hydroxylase activity in the chicken embryo in ovo

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