Detail of "786-66-3"

Reference

A comparative examination of the in vitro metabolism of five cyclopenta[a]phenanthrenes of varying carcinogenic potential

A comparative examination of the in vitro metabolism of five cyclopenta[a]phenanthrenes of varying carcinogenic potential. Coombs, Maurice M.; Russell, Jeremy C.; Jones, John R.; Ribeiro, Odartey (Chem. Lab., Imp. Cancer Res. Fund, London WC2A 3PX, UK). Carcinogenesis (London), 6(8), 1217-22 (English) 1985. CODEN: CRNGDP. ISSN: 0143-3334. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) Section cross-reference(s): 2 Metabolites of 15,16-dihydrocyclopenta[a]phenanthren-17-one (I) [786-66-3] and its 1- (II) [85616-38-2] and 12-Me [789-46-8] homologs (all noncarcinogens) along with those from the 11-Me [892-17-1] and 11,12-dimethyl-17-ketone [894-52-0] (carcinogens), produced in vitro by hepatic microsomes from methylcholanthrene-induced rats, were sepd. by reverse phase HPLC. Identifications of individual metabolites were based upon elution times, UV spectra, and in some cases by mass spectrometry, CD, and identity with synthetic derivs. All 5 compds. were biol. oxidized at their terminal A and D rings to yield 1,2-dihydrodiols and 15- and 16- ols; with the exception of the II all also gave similar amts. of 3,4-dihydrodiols. II by contrast failed to produce this metabolite, furnishing instead the 4-phenol and 5 other, probably related phenolic derivs. Previous work has established that for the 11-methyl-17-ketone, the 3,4-dihydrodiol is the proximate carcinogen. Thus, whereas lack of biol. activity with the II can be ascribed to its failure to produce a 3,4-dihydrodiol, in the case of the unsubstituted parent ketone and its 12-Me deriv. other detg. factors must come into play.

Comparison of the binding of some carcinogenic and non-carcinogenic cyclopenta[a]phenanthrenes to DNA in vitro and in vivo

Comparison of the binding of some carcinogenic and non-carcinogenic cyclopenta[a]phenanthrenes to DNA in vitro and in vivo. Russell, Jeremy C.; Bhatt, Tarlochan S.; Jones, John R.; Coombs, Maurice M. (Dep. Chem., Univ. Surrey, Guildford/Surrey GU2 5XH, UK). Carcinogenesis (London), 6(8), 1223-5 (English) 1985. CODEN: CRNGDP. ISSN: 0143-3334. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) After microsomal activation in vitro, both the strong carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one (I) [892-17-1] and its inactive 12-Me isomer [789-46-8] bind covalently to added DNA, in the ratio ~6:1 (1595 and 254 mmol/mol of DNA P, resp.). Binding (>100-fold) was obsd. when DNA was isolated from the skin of mice that had received a topical dose of 1000 nmol of the 2 compds., and of the unsubstituted ketone [786-66-3] (noncarcinogen) and its 11,12-dimethyl deriv. [894-52-0] (carcinogen), 48 h previously; the binding ratios were 458, 155, 19, and 974 nmol/mol DNA P, resp. Covalent binding of I to mouse skin DNA, measured 48 h after topical application, was linear with dose over the range 50-1000 nmol. It has previously been demonstrated in mice initiated with 200 or 400 nmol of I and promoted by repeated application of croton oil that skin tumor incidences were 50 and 70%, resp. For a topical dose of 1000 nmol of the inactive 12 Me isomer DNA binding in skin falls in this range, equiv. to DNA binding given by ~340 nmol of the carcinogen. Thus, although the inactive unsubstituted parent compd. essentially fails to bind to skin DNA after topical application, there does not seem to be a consistent relationship between extent of DNA binding in vivo and carcinogenicity among these cyclopenta[a]phenanthrenes. However, loss of the 12-Me adducts from skin followed a logarithmic course over the 1st 10 days following application, with a half life of 3.5 days. In contrast, it was previously shown that removal of the 11-Me adducts could not be measured above the normal rate of DNA turnover for this mouse tissue (half-life 6-7 days). Apparently, active DNA repair of the 12-Me lesions contributes to the lack of activity of this isomer.