The use of quantitative histological and molecular data for risk assessment and biologically based model development

被引:3
作者
Andersen, ME [1 ]
机构
[1] Colorado State Univ, Int Ctr Risk Assessment, Ft Collins, CO 80523 USA
关键词
tumor promotion; 2,3,7,8-tetrachlorodibenzo-p-dioxin; dioxin; immunohistochemistry; phenotypic switching; regional induction; cell proliferation;
D O I
10.1080/01926230252824789
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
In organs with diverse cell populations, it is not uncommon for one type of cell to respond while others are spared. Even in an organ with common cell types, such as hepatocytes within the liver, the population of cells may respond with different sensitivities for injury or for biochemical responses to toxicants. In the liver, many tumor promoters induce cytochrome P450 enzymes and other proteins in centrilobular cells at much lower doses than required to cause induction in periportal cells. In addition, these induction responses appear to occur at the level of individual cells-a 50% response of the liver for induction does not represent 50% induction in all cells. Instead, half of the cells are fully induced and half are unaffected. Cells "switch" from one phenotypic state to another. Over the past 10 years, several attempts have been made to model these cellular switches and to understand their relevance for hepatic tumor promotion and risk assessment. The data used for analyzing these switches include responses of the entire liver (total induction), responses of individual cells in the liver (regional induction), and cellular responses such as proliferation and apoptosis. This brief overview describes the development of biologically based, dose-response (BBDR) models for protein induction and tumor promotion in liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with emphasis on the role of specific types of histological and molecular data in providing insights about mechanisms for cellular switches and their implications for tumor promotion. As the biological basis of these switches become unraveled and incorporated into the models, these BBDR models should eventually serve to improve risk assessments with a variety of liver tumor promoters with receptor-based modes of action.
引用
收藏
页码:106 / 111
页数:6
相关论文
共 29 条
[1]   NEGATIVE SELECTION IN HEPATIC TUMOR PROMOTION IN RELATION TO CANCER RISK ASSESSMENT [J].
ANDERSEN, ME ;
MILLS, JJ ;
JIRTLE, RL ;
GREENLEE, WF .
TOXICOLOGY, 1995, 102 (1-2) :223-237
[2]   Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation [J].
Andersen, ME ;
Birnbaum, LS ;
Barton, HA ;
Eklund, CR .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1997, 144 (01) :145-155
[3]  
ANDERSENME, 1998, BELLE NEWSLETTER, V7, P2
[4]  
ANDERSON JM, 1993, J ANAL, V1, P13
[5]   DOSE-DEPENDENT ACINAR INDUCTION OF CYTOCHROMES-P450 IN RAT-LIVER - EVIDENCE FOR A DIFFERENTIAL MECHANISM OF INDUCTION OF P450IA1 BY BETA-NAPHTHOFLAVONE AND DIOXIN [J].
BARS, RG ;
ELCOMBE, CR .
BIOCHEMICAL JOURNAL, 1991, 277 :577-580
[6]   INDUCTION OF CYTOCHROME-P-450 IN CULTURED RAT HEPATOCYTES - THE HETEROGENEOUS LOCALIZATION OF SPECIFIC ISOENZYMES USING IMMUNOCYTOCHEMISTRY [J].
BARS, RG ;
MITCHELL, AM ;
WOLF, CR ;
ELCOMBE, CR .
BIOCHEMICAL JOURNAL, 1989, 262 (01) :151-158
[7]   LOCALIZATION AND DIFFERENTIAL INDUCTION OF CYTOCHROME-P450IVA AND ACYL-COA OXIDASE IN RAT-LIVER [J].
BELL, DR ;
BARS, RG ;
GIBSON, GG ;
ELCOMBE, CR .
BIOCHEMICAL JOURNAL, 1991, 275 :247-252
[8]   Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: Evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter [J].
Conolly, RB ;
Andersen, ME .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1997, 146 (02) :281-293
[9]   COMPUTER-SIMULATION OF CELL-GROWTH GOVERNED BY STOCHASTIC-PROCESSES - APPLICATION TO CLONAL GROWTH CANCER MODELS [J].
CONOLLY, RB ;
KIMBELL, JS .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1994, 124 (02) :284-295
[10]  
HALL JC, 1990, ANNU REV GENET, V24, P659