The development and characterization of many inbred, congenic, and recombinant strains of rats in recent years has led to the detailed genetic description of this species, especially in regard to its major histocompatibility complex. This information has contributed substantially to the study of comparative genetics and has greatly enhanced the utility of the rat in a variety of areas of biomedical research. This article focuses on the use of the rat in immunogenetics, transplantation, cancer-risk assessment, cardiovascular diseases, and behavior.

Two cytochromes P450 (PB1 and PB2) have been isolated from the livers of rats treated with phenobarbital. PB2 (mol. wt. 53 500) is novel and is the first example of a phenobarbital-inducible enzyme with a Soret peak at 447 nm. Using an enzyme-linked immunosorbent assay, some immunochemical and structural similarities were observed between these cytochromes. PB1 and PB2 were induced by phenobarbital, Aroclor 1254, trans-stilbene oxide and to a lesser extent by isosafrole. Immunohistochemical localization of these proteins in the liver of untreated rats showed PB1 to be localized in a large area and PB2 in a narrow range of cells around the central vein. This demonstrates the heterogeneity of hepatocytes even within the centrilobular area and indicates that the synthesis of these two proteins is regulated differently although both are induced by the same agent, phenobarbital. Two 3-methylcholanthrene inducible cytochromes MC1 (mol. wt. 54 500) and MC2 (mol. wt. 57 000) were present at very low levels, MC2 mostly in the periportal region but also diffusely distributed throughout the lobule including some centrilobular cells, MC1 concentrated in the centrilobular region. The localization of two major groups of glutathione transferases (GST's) was also different. 'C' type proteins (Yb Yb') and microsomal epoxide hydrolase (EH), were concentrated around the central vein, whereas the 'B' type proteins (Ya Yc) and cytochrome P450 reductase were distributed in a larger area of this region. Thus, the localization was different for some members of the same enzyme family, whilst similarities in the localization existed across the border of the families: (i) PB2, MC1, EH and GST 'C' type proteins were concentrated in a narrow area around the central vein; (ii) PB1 and GST 'B' type proteins occupied a large centrilobular area; (iii) MC2 levels were very low, predominantly periportal but also diffusely distributed throughout the lobule. Treatment of the animals with inducers increased the staining intensity and in several cases extended the areas of cells containing these proteins over the adjacent zone without fundamentally altering their distributions. However, treatment with beta-naphthoflavone led to a shift of MC1 to the periportal area. This suggests that the expression of these proteins in certain cells is not an irreversible quality of differentiation but depends on the degree of suppression and derepression of regulatory components.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytochrome P-450s are a superfamily of haem-containing proteins involved in the metabolism of foreign compounds, as well as a variety of endogenous molecules. The hepatic levels and function of this diverse group of enzymes are determined by both constitutive and xenobiotic regulators. To examine the role of constitutive factors in cytochrome P-450 regulation, the levels of three distinct groups of phenobarbital-inducible hepatic cytochrome P-450s were studied following dexamethasone-treatment or hypophysectomy. In the mouse, dexamethasone was a potent inducer of proteins within the PB1 (subfamily IIC), PB2c (family III) and PB3 (subfamily IIB) families. These findings were strikingly different from the effects in the rat where essentially no effect on PB3 expression and indeed suppression of proteins related to PB1 was observed. Determination of mRNA concentration indicated that the difference was at the level of transcription. These findings indicate that synthetic glucocorticoids have the potential to be potent phenobarbital-like inducing agents. In the mouse hypophysectomy, like dexamethasone, induced hepatic mRNA of P-450 from families P-450IIB, P-450IIC and P-450III. Again a species difference was observed as this treatment had essentially no effect in the rat. These data in the mouse indicate that factors produced in the pituitary can either affect the transcription rate of phenobarbital and dexamethasone-inducible P-450 genes or influence the stability of their mRNAs.

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Major histocompatibility complex (MHC)-linked deletions in the rat are associated with defects in growth and development and increased susceptibility to chemical carcinogens. The present study maps a locus critical for determining susceptibility to diethylnitroamine (DEN) carcinogenesis by using two groups ofMHC-recombinant rats congenic for the MHC and its linked region. Resistance to DEN segregates with a locus (rec+) that maps between RTL.E and ft, and its homozygous loss markedly increases susceptibility to DEN. Non-MHC genes do not significantly influence the susceptibility of these strains to DEN. The existence of the rec locus adds support to our hypothesis that some genes in the MHC-linked region play a major role in both normal and abnormal growth.The role of hereditary factors in the susceptibility to cancer was first proposed in 1866 by Brocca (1), who documented the general susceptibility to cancer in his family. Similar observations have been made periodically since then (2), and recently they have been documented by detailed epidemiological studies (3,4). A variety of human malignancies have been associated with genes of the major histocompatibility complex (MHC) (5), and some of these malignancies have been associated with deletions in chromosome 6, which carries the MHC, either exclusively (6, 7) or in association with other deletions (5). At the molecular level, deletion of tumor-suppressor genes and activation of oncogenes have been demonstrated in humans and in experimental animals (8, 9).We have developed the hypothesis that MHC-linked genes, or genetic defects, influence reproduction, development, and susceptibility to chemical carcinogens (10, 11) on the basis of experimental work in rats (12)(13)(14) and clinical studies in humans (15)(16)(17). Deletions in the MHC-linked region derived from the BIL/1 strain (grc-) ( Fig. 1) exposure to dimethylbenzanthracene, whereas the ACP strain does not. There is no evidence for an immune defect in the grc rats as a basis for their tumor susceptibility because they can make normal antibody responses to synthetic polypeptide antigens and to skin grafts and display normal firstand second-set rejection of allogeneic skin grafts (33-35).The present study was undertaken to map the critical MHC-linked locus affecting susceptibility to DEN carcinogenesis and to rule out a significant effect on susceptibility of non-MHC genes by using two sets ofinbred and recombinant rats congenic for the MHC plus the MHC-linked region or for the MHC-linked region alone. MATERIALS AND METHODSCongenic Strains. The pedigrees of the strains are shown in Fig. 1 1967The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.