title: N-nitrosodiethylamine  genotoxicity  evaluation: a cytochrome P450 induction study in rat  hepatocytes.
abstract: In  rats, N-nitrosodiethylamine (NDEA) induces tumors mainly in the liver.  This could be because various enzymes are responsible for the metabolic  activation of NDEA, besides the hepatic NDEA metabolizing enzyme, CYP2E1. We  examined NDEA genotoxicity and cytotoxicity in primary cultures of female rat  hepatocytes; we also looked at how it affected CYP mRNA expression. Single  incubation with 0.9% NaCl resulted in a mean of 0.2% apoptotic cells, which  doubled with 105 μg  NDEA/mL. The frequency of necrosis with NDEA treatment was also doubled.  Besides the cytotoxic effects, there was also a 4-fold decrease in mitotic  index and a 3-fold decrease in the percentage of cells with micronuclei. A  significant increase in micronucleus cells when hepatocytes were incubated with  2.1 μg NDEA/mL suggests  that DNA repair was inactive. The chromosomal aberration evaluation revealed a  discrete dose-response curve. Treatment with NDEA induced increases in CYP  mRNA: CYP2B2 (1.8 times) and CYP2E1 (1.6 times) with non-cytotoxic NDEA  concentrations (0.21-21 μg/mL).  CYP2B1 mRNA levels decreased at 0.21 μg NDEA/mL (2.5-fold), while CYP4A3 mRNA decreased  1.3-fold. NDEA treatment at 2.1 μg/ mL induced a 1.9-fold increase in CYP3A1 mRNA.  Understanding the cumulative effects in target cells during precarcinogenesis  is crucial to understanding the mode of action of potential carcinogens and in  order to develop comprehensive chemical toxicity profiles.
authors: Department of Cell Biology, Division of Genetics, Salzburg University, Salzburg, Austria. aiub@hotmail.com
authors: C A F
authors: CA
authors: Aiub
authors: G
authors: G
authors: Gadermaier
authors: I O
authors: IO
authors: Silva
authors: I
authors: I
authors: Felzenszwalb
authors: L F R
authors: LF
authors: Pinto
authors: F
authors: F
authors: Ferreira
authors: P
authors: P
authors: Eckl
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004249:DNA Damage / Q000187:drug effects*; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D009336:Necrosis / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger; D051381:Rats; D011916:Rats, Inbred F344; D013250:Steroid Hydroxylases / Q000096:biosynthesis*
chemical_list: D000477:Alkylating Agents; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C025619:steroid 16-beta-hydroxylase