Abstract
Cultured rat hepatocytes were challenged with benzo[a]pyrene (BaP; 0.3-30 μM), naphthalene (NAPH; 0.1-100 μM), 2-methylnaphthalene (2-MNAPH; 0.1-100 μM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001-1nM), 2,3,7,8-tetrachlorodibenzofuran (TCDF; 0.005-5nM) or pentachlorophenol (PCP; 0.1-100 μM) for 4-24 hr to define class-specific differences in hepatotoxic potential. Mitochondrial fragility and GSH status were monitored as indices of hepatocyte injury. A 4-hr challenge with BaP and PCP increased mitochondrial fragility in a concentration-dependent manner, while TCDD and TCDF elicited erratic increases, and NAPH and 2-MNAPH were without effect. Preatment of hepatocytes with 250 μM diamide enhanced the mitochondrial toxicity of BaP. The aryl hydrocarbon receptor agonists upregulated hepatocyte GSH levels by 24 hr, a response which in the case of BaP was preceded by varying degrees of GSH depletion between 6 to 16 hr. NAPH and 2-MNAPH transiently decreased hepatocyte GSH levels at 12 hr, but were without effect at later time points, while PCP did not modulate hepatocyte GSH levels. Modulation of hepatocyte GSH by BaP and TCDD was antagonized by 10 μM α-naphthoflavone. These data implicate oxidative mechanisms and aryl 1 hydrocarbon receptor signalling in aromatic hydrocarbon hepatotoxicity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 175-182 |
| Number of pages | 8 |
| Journal | Toxicology in Vitro |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1998 |
| Externally published | Yes |
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Keywords
- Ah receptor
- Aromatic hydrocarbons
- Free radicals
- Glutathione
- Hepatocytes
- LDH leakage
- Mitochondrial fragility
ASJC Scopus subject areas
- Toxicology
Cite this
Cytotoxic response profiles of cultured rat hepatocytes to selected aromatic hydrocarbons. / Zhao, W.; Ramos, Kenneth.
In: Toxicology in Vitro, Vol. 12, No. 2, 04.1998, p. 175-182.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cytotoxic response profiles of cultured rat hepatocytes to selected aromatic hydrocarbons
AU - Zhao, W.
AU - Ramos, Kenneth
PY - 1998/4
Y1 - 1998/4
N2 - Cultured rat hepatocytes were challenged with benzo[a]pyrene (BaP; 0.3-30 μM), naphthalene (NAPH; 0.1-100 μM), 2-methylnaphthalene (2-MNAPH; 0.1-100 μM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001-1nM), 2,3,7,8-tetrachlorodibenzofuran (TCDF; 0.005-5nM) or pentachlorophenol (PCP; 0.1-100 μM) for 4-24 hr to define class-specific differences in hepatotoxic potential. Mitochondrial fragility and GSH status were monitored as indices of hepatocyte injury. A 4-hr challenge with BaP and PCP increased mitochondrial fragility in a concentration-dependent manner, while TCDD and TCDF elicited erratic increases, and NAPH and 2-MNAPH were without effect. Preatment of hepatocytes with 250 μM diamide enhanced the mitochondrial toxicity of BaP. The aryl hydrocarbon receptor agonists upregulated hepatocyte GSH levels by 24 hr, a response which in the case of BaP was preceded by varying degrees of GSH depletion between 6 to 16 hr. NAPH and 2-MNAPH transiently decreased hepatocyte GSH levels at 12 hr, but were without effect at later time points, while PCP did not modulate hepatocyte GSH levels. Modulation of hepatocyte GSH by BaP and TCDD was antagonized by 10 μM α-naphthoflavone. These data implicate oxidative mechanisms and aryl 1 hydrocarbon receptor signalling in aromatic hydrocarbon hepatotoxicity.
AB - Cultured rat hepatocytes were challenged with benzo[a]pyrene (BaP; 0.3-30 μM), naphthalene (NAPH; 0.1-100 μM), 2-methylnaphthalene (2-MNAPH; 0.1-100 μM), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001-1nM), 2,3,7,8-tetrachlorodibenzofuran (TCDF; 0.005-5nM) or pentachlorophenol (PCP; 0.1-100 μM) for 4-24 hr to define class-specific differences in hepatotoxic potential. Mitochondrial fragility and GSH status were monitored as indices of hepatocyte injury. A 4-hr challenge with BaP and PCP increased mitochondrial fragility in a concentration-dependent manner, while TCDD and TCDF elicited erratic increases, and NAPH and 2-MNAPH were without effect. Preatment of hepatocytes with 250 μM diamide enhanced the mitochondrial toxicity of BaP. The aryl hydrocarbon receptor agonists upregulated hepatocyte GSH levels by 24 hr, a response which in the case of BaP was preceded by varying degrees of GSH depletion between 6 to 16 hr. NAPH and 2-MNAPH transiently decreased hepatocyte GSH levels at 12 hr, but were without effect at later time points, while PCP did not modulate hepatocyte GSH levels. Modulation of hepatocyte GSH by BaP and TCDD was antagonized by 10 μM α-naphthoflavone. These data implicate oxidative mechanisms and aryl 1 hydrocarbon receptor signalling in aromatic hydrocarbon hepatotoxicity.
KW - Ah receptor
KW - Aromatic hydrocarbons
KW - Free radicals
KW - Glutathione
KW - Hepatocytes
KW - LDH leakage
KW - Mitochondrial fragility
UR - http://www.scopus.com/inward/record.url?scp=0032055487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032055487&partnerID=8YFLogxK
U2 - 10.1016/S0887-2333(97)00099-4
DO - 10.1016/S0887-2333(97)00099-4
M3 - Article
C2 - 20654398
AN - SCOPUS:0032055487
VL - 12
SP - 175
EP - 182
JO - Toxicology in Vitro
JF - Toxicology in Vitro
SN - 0887-2333
IS - 2
ER -