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SITE VISIT GRANIEE: Edward Bresnick, Ph.D. Director, Eppley Institute University of Nebraska, Omaha, Nebraska Grant Application No. 1369R2 "Expression of Cytochrome P450c" SITE VISITORS: Drs. Ford, Lynch and Stone DATE OF VISIT: October 20, 1983 BACKGROCIDID Dr. Bresnick has been supported by CTR since July 1, 1981 in studies designed to elucidate regulatory mechanisms involved in gene transcription and messager RNA translation to cytochrome P450's in the activation (and detoxification) of polycyclic arunatic amines. Dr. Bresnick recently moved from the University of Vermont (Burlington, Vt.) to his present location: Also moving with him were two manbers of the 'group working in this program, Dr. Robert N. Hines and Robert Foldes, a second year graduate student. DISCUSSION The overall area of interest is in the activation of PAH's to the ultimate carcinogenic form: PAH -- ARENE P450 OXIDE Phenol Hydrase DIOL EPOXIDE TARGET TISSUE(S) The main effort is in the understanding of regulatory processes at three major areas: (a) at the gene transcriptional level. (b) at the level of processing of the precursor "neonatal' messager.RNA to an 'adult' form, and

- 2 - (c) at the level of transport of the adult message fran the nucleus to the cytoplasn. This is indicated as follows: Cytoplasnic Events PAH + PAH.protein cytosolic ! 1 protein l Nuclear Events Induction of: (Large neonatal' molecules) Precursor m RNA. I P450 Protein Product Translation of Message 5'.Methylguanine Cap I (snaller 'adult' molecule) m RNA Messen e Processing m.RNA - 3' - poly A tail 1 TRANSPORT Cap-m RNA.poly A Dr. Bresnick is anploying 3MC and phenobarbital as inducers of P450 c and P450.b, respectively. 3 MC induces P450 c and a little P450 d Phenobarbital induces P450.b and a little P450 c

- 3 - (Note: so far about 11 P450's have been identified -- there may be hundreds). Ecploying a bacterial plasmid (PBR 322)c,-DNA probes are being developed in order to be able to examine the expression of m ttNA (that is, amount of tissue m.RNA) for P450 c and P450 d in early developing rat liver and livers fran older rats. (Note - rat probes x-react with human P450 c). CONCLUDING RIMARKS Dr. Bresnick offered two reprints (published in 1983) and two manuscripts as an indication of his continuing productivity. (Abstracted copies are attached). It is difficult to assess the effects of his new position and duties on future research efforts, but he will be applying to CTR for a continuation grant, and the feeling of the site-visitors is that he and his group will continue their investigations without significant changes in effort. D. FORD/D. STOiM /am