Metabolic activation of 2-aminofluorene in extrahepatic rat tissues: involvement of peroxidases and of cytochrome P-450

1 The in vitro metabolism ofn-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydro xylated metabolites ofn-hexane were quantified by gas chromatography-mass spectometry. 2 Rat liver and extensor digitorum longus (EDL, fast- twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined. 3 Inhibition of 2- and 3-hexanol production from n- hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activ ity. 4 Production of all three hexanols was significantly increased with phenobarbital-induced rat liver micro somes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain micro somes was observed. No increase in n-hexane meta bolism was noted following induction with β- naphthoflavone or with ethanol.

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EFFECTS OF MOTORCYCLE EXHAUST ON CYTOCHROME P-450-DEPENDENT MONOOXYGENASES AND GLUTATHIONE S-TRANSFERASE IN RAT TISSUES

Journal of Toxicology and Environmental Health Part A ◽

10.1080/009841098158674 ◽

1998 ◽

Vol 54 (7) ◽

pp. 509-527 ◽

Cited By ~ 19

Author(s):

Tzuu-Huei Ueng Wen-Po Hwang Ruei-Mi

Keyword(s):

Rat Tissues ◽

Glutathione S Transferase ◽

Cytochrome P 450

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Metabolic activation of the tricyclic antidepressant amineptine by human liver cytochrome P-450

Biochemical Pharmacology ◽

10.1016/0006-2952(87)90614-9 ◽

1987 ◽

Vol 36 (14) ◽

pp. 2421-2424 ◽

Cited By ~ 17

Author(s):

Jean Genève ◽

Dominique Larrey ◽

Gilles Amouyal ◽

Jacques Belghiti ◽

Dominique Pessayre

Keyword(s):

Human Liver ◽

Metabolic Activation ◽

Tricyclic Antidepressant ◽

Liver Cytochrome ◽

Cytochrome P 450

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Testosterone-mediated regulation of mouse renal cytochrome P-450 isoenzymes

Biochemical Journal ◽

10.1042/bj2660675 ◽

1990 ◽

Vol 266 (3) ◽

pp. 675-681 ◽

Cited By ~ 35

Author(s):

C J Henderson ◽

A R Scott ◽

C S Yang ◽

C R Wolf

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Sex Differences ◽

Metabolic Activation ◽

Gene Families ◽

Mouse Kidney ◽

Environmental Chemicals ◽

Carcinogenic Effects ◽

Cytochrome P 450 ◽

Androgen Levels

We have studied the extent to which mouse renal cytochrome P-450 isoenzymes are sexually differentiated, and the factor(s) regulating this dimorphism. Intriguingly, sex differences were not seen in the expression of a single cytochrome P-450 enzyme, but were observed in the expression of all P-450 isoenzymes detectable, encoded by six gene families or sub-families. This effect was mediated by testosterone, which had the capacity to both induce and repress P-450 gene expression, and which was independent of growth hormone. The changes in protein content were mirrored in all but one case by changes in the levels of mRNA, indicating that these genes contain hormone-responsive elements. These findings are consistent with numerous reports of sex differences in the susceptibility of the mouse kidney to the toxic and carcinogenic effects of drugs and environmental chemicals, many of which are metabolized to cytotoxic products by the cytochrome P-450-dependent mono-oxygenases. These data imply that circulating androgen levels will be an important factor in susceptibility of the kidney to toxic or carcinogenic compounds which require metabolic activation.

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