Effect of estrogenic perturbations on delta-aminolevulinic acid-induced porphobilinogen deaminase and protoporphyrin IX levels in rat Harderian glands, liver, and R3230AC tumors

The Harderian gland in rodents highly expresses enzymes of the heme biosynt hetic pathway that are responsible for porphyrin production. Interestingly, many of the steps in Harderian gland heme biosynthesis, including protopor phyrin production, are controlled hormonally. We hypothesized that estrogen ic alterations, ovariectomy or tamoxifen administration, might also alter t he response of porphobilinogen deaminase activity and/or protoporphyrin IX production to delta-aminolevulinic acid administration in the hormonally re sponsive R3230AC rat mammary adenocarcinoma. We also determined whether the response of the R3230AC tumor, borne on ovariectomized hosts, to delta-ami nolevulinic acid-based photodynamic therapy was altered compared with tumor s treated on intact hosts. Ovariectomy of female Fischer rats bearing the h ormonally responsive R3230AC mammary adenocarcinoma caused a significant re duction in delta-aminolevulinic acid-induced protoporphyrin IX levels and p orphobilinogen deaminase activity in tumors compared with levels in tumors from intact animals treated with sl aminolevulinic acid. In contrast, altho ugh porphobilinogen deaminase activity in the Harderian gland from ovariect omized animals was reduced significantly compared with that in glands from intact animals, protoporphyrin IX levels were unaltered. Administration of the anti-estrogen tamoxifen to tumor-bearing rats resulted in a significant increase in porphobilinogen deaminase in both tumor and Harderian gland. A lthough administration of delta-aminolevulinic acid increased protoporphyri n IX levels in Harderian glands in tamoxifen-treated animals, tumor levels of protoporphyrin IX remained unaltered in the tamoxifen-treated rats. Trea tment of R3230AC tumors with delta-aminolevulinic acid based photodynamic t herapy in ovariectomized rats resulted in a significantly reduced response compared with the same treatment regimen in intact animals, 4.9 +/- 0.39 ve rsus 10.6 +/- 0.6 days to reach twice the initial tumor volume, respectivel y. These results indicate that the hormonal status of the host should be co nsidered when treating hormonally sensitive tumors with delta-aminolevulini c acid-based photodynamic therapy. BIOCHEM PHARMACOL 58;11:1821-1829, 1999. (C) 1999 Elsevier Science Inc.