Unscheduled DNA Synthesis Test in Liver Cells

Purpose. The purpose of the ex vivo unscheduled DNA synthesis (UDS) test on mammalian liver cells is to evaluate the potential of the test substance to induce DNA excision repair in liver cells of treated animals (usually rodents and preferably rats). An increase in UDS activity is indicative of primary DNA damage and subsequent excision repair (Butterworth et al. 1987 Mirsalis and Butterworth 1980 Mirsalis et al. 1982). 

Regulatory Acceptance. The UDS test on mammalian liver cells is weU-validated and widely accepted by regulatory agencies. The optimal expai-mental conditions and rules for data interpretation have been published in OECD guideline 486. 

Liver is the preferred tissue for UDS measurement because it is well-perfused and the main metabolic site for absorbed compounds (during first-pass of compounds administered by the oral and intraperitoneal routes). Moreover, it is a slow-dividing tissue, and only a small proportion of cells undergo replicative DNA synthesis. Therefore DNA synthesis in most liver cells is limited to DNA repair (Butterworth et al. 1987 Mirsalis and Butterworth 1980). 

Like tests done with bone marrow, the Uvct UDS test has limited value for the detection of labile direct-acting compoimds, which cannot readily reach the liver. 

Site-of-contact tissues might be preferable for such compounds (Burlinson 1989 Furihata et al. 1984 Furihata and Matsushima 1987 Mori et al. 1999 Sawyer et al. 1988), if sufficiently validated. The main technical limitation of this assay with respect to other tissues is the need to isolate the cells after in vivo treatment and to get them to incorporate tritiated thymidine in vitro. Because UDS measurement does not require cell division, it can potentially be applied to many different tissues, provided that the cells can be isolated and maintained in primary culture for the few hours required for tritiated thymidine incorporation. The literature contains reports of UDS-based studies of stomach, colon, kidney, pancreas, tracheal epithelium, nasal epithelium, epidermis, keratinocytes, and spermatocytes (Burlinson 1989 Furihata et al. 1984 Furihata and Matsushima 1987 Sawyer et al. 1988 Loury et al. 1987 Mori et al. 1999 Latt et al. 1981 Helleday 2003). 

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