Inducible cytochrome P450 activities in renal glomerular mesangial cells: Biochemical basis for antagonistic interactions among nephrocarcinogenic polycylic aromatic hydrocarbons

M. H. Falahatpisheh, J. Kevin Kerzee, R. P. Metz, K. C. Donnelly, Kenneth Ramos

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. Methods: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 - 30 μM) or in the presence of ANTH (3 μM) or CHRY (3 μM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). Results: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. Conclusion: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential.

Original languageEnglish (US)
JournalJournal of Carcinogenesis
Volume3
DOIs
StatePublished - Aug 17 2004
Externally publishedYes

Fingerprint

Aromatic Hydrocarbons
Mesangial Cells
Hydrocarbons
Cytochrome P-450 Enzyme System
Polycyclic Aromatic Hydrocarbons
Toxicity
Aryl Hydrocarbon Hydroxylases
Messenger RNA
Cytochrome P-450 CYP1A1
Proteins
Metabolome
Benzo(a)pyrene
High performance liquid chromatography
Cytochromes
Metabolism
Carcinogenesis
Epithelial Cells
High Pressure Liquid Chromatography
RNA
Kidney

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cancer Research
  • Medicine(all)

Cite this

Inducible cytochrome P450 activities in renal glomerular mesangial cells : Biochemical basis for antagonistic interactions among nephrocarcinogenic polycylic aromatic hydrocarbons. / Falahatpisheh, M. H.; Kerzee, J. Kevin; Metz, R. P.; Donnelly, K. C.; Ramos, Kenneth.

In: Journal of Carcinogenesis, Vol. 3, 17.08.2004.

Research output: Contribution to journalArticle

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abstract = "Background: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. Methods: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 - 30 μM) or in the presence of ANTH (3 μM) or CHRY (3 μM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). Results: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. Conclusion: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential.",
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