Metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol in human mammary epithelial cells: feedback inhibition by 7-hydroxybenzo[a]pyrene.

The metabolism of benzo[a]pyrene (B[a]P) and (-)-transbenzo[a]pyrene-7,8-dihydrodiol (B[a]P-diol) was compared in human mammary epithelial cells (HMEC) grown in serum-free medium, MCDB-170. Conversion of B[a]P-diol to the carcinogen (+)-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide (BPDE), as measured by analysis of their tetraol hydrolysis products, occurred much more efficiently in cultures incubated with [3H]B[a]P-diol than in cultures incubated with [3H]B[a]P. In cultures pretreated with unlabeled B[a]P (24 h, 400 nM), the conversion of [3H]-B[a]P-diol to [3H]tetraols is inhibited 49%, while the conversion of [3H]B[a]P to [3H]B[a]P-diol- is not affected. These observations led to the identification of a major B[a]P-derived metabolite as 7-hydroxybenzo[a]pyrene (B[a]P-7-ol), which was found to be an extremely potent and selective inhibitor of the conversion of B[a]P-diol to BPDE, with a KI estimated at 3-12 nM. Thus B[a]P activation in HMEC appears to be significantly limited by a feedback inhibition pathway induced by B[a]P-7-ol. The potency and selectivity of the B[a]P-7-ol-induced inhibition suggests that the diol to diolepoxide conversion is affected by a selective oxygenase in HMEC, rather than a non-enzymatic, peroxy radical-induced mechanism. B[a]P-7-ol should prove to be a valuable tool in the study of B[a]P carcinogenesis.

Inhibition of adenocarcinoma TA3 ascites tumor growth by rifamycin derivatives.

A growth inhibitory effect on adenocarcinoma TA3 ascites tumors in LAF1/J mice resulted from the repeated IP administration of subtoxic doses of 3 rifamycin derivatives: rifampicin (Rif)1, dimethylbenzyldesmethylrifampicin (DMB), and rifazone-82 (R-82). A high-viscosity methylcellulose vehicle was found to be essential for obtaining a uniform drug suspension and a significant antitumor effect by the least water soluble derivatives, DMB and R-82. The more hydrophilic derivative, Rif, was found to have a comparable growth inhibitory effect on TA3 cells when prepared in 0.9% NaCl solution with or without added methylcellulose. Oral or SC drug injections did not have an antitumor effect. The results of this study point to the importance of vehicle and route of administration in chemotherapy trials with these compounds.

Preferential inhibition of the growth of virus-transformed cells in culture by rifazone-82, a new rifamycin derivative.

Rifazone-8(2), a new rifamycin derivative, is shown to preferentially inhibit the growth of virus-transformed chick cells in culture. Macromolecular synthesis and glucose uptake of transformed cells are also appreciably decreased in the presence of low concentrations of rifazone-8(2) where the normal cells appear unaffected. While rifazone-8(2) is shown to be a selective inhibitor of RNA-directed DNA polymerase in vitro, its action on the growth of transformed cells may involve some other mechanism.

Inhibition of three nucleotide polymerases by rifamycin derivatives.

It is possible to design rifamycin derivatives which can distinguish between viral RNA-instructed DNA polymerase and other nucleotide polymerases.