Phorbol ester induction of 8-lipoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation but not ornithine decarboxylase induction.
Several responses suggested to be critical components of phorbol ester tumor promotion were compared in 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion-sensitive SSIN and TPA promotion-resistant C57BL/6J mice. SSIN mice treated topically with 2 micrograms of TPA showed extensive hyperplasia accompanied by edema, measured as a 26% increase in water content of the skin. Only a very slight hyperplasia and 7% increased water content occurred after TPA treatment of C57BL/6J mice. The induction of ornithine decarboxylase was determined to be the same both in vivo and in vitro for SSIN and C57BL/6J mice, which does not correlate with the histological observations. Because hyperplasia and inflammation can be mediated by arachidonic acid metabolites, it was hypothesized that differences in this metabolic pathway would correlate with the histological responses. No significant qualitative or quantitative differences, however, were observed in the profiles of the major cyclooxygenase products between the strains of mice. Prostaglandin E2, the principal prostaglandin, was synthesized at a 3-fold greater level than prostaglandins D2 or F2 alpha in response to TPA. The most abundant lipoxygenase product was 12-hydroxyeicosatetraenoic acid followed by 8-, 15-, and 5-hydroxyeicosatetraenoic acid. 8-Lipoxygenase activity is elevated 24 h after TPA treatment in the SSIN mice by approximately 4-fold; no elevation is seen in C57BL/6J mice. A comparison of the oxidant response to TPA as well as to phospholipase C showed that SSIN epidermal cells generated a higher level, measured by chemiluminescence, than C57BL/6J cells. This suggests that oxidant generation or possibly 8-lipoxygenase activity may be the basis for the sensitivity or resistance to TPA as a hyperplasiogen and as a tumor promoter.
Fischer
S M
SM
University of Texas System Cancer Center, Science Park-Research Division, Smithville 78957.
Baldwin
J K
JK
Jasheway
D W
DW
Patrick
K E
KE
Cameron
G S
GS
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000096:biosynthesis*; D002851:Chromatography, High Pressure Liquid; D004487:Edema / Q000139:chemically induced; D004790:Enzyme Induction / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006965:Hyperplasia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000502:physiology*; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D010703:Phorbol Esters / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D012871:Skin Diseases / Q000139:chemically induced* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D006893:Hydroxyeicosatetraenoic Acids; D010703:Phorbol Esters; D011453:Prostaglandins; D001091:Arachidonate Lipoxygenases; C054192:arachidonate 8-lipoxygenase; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate