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PubMed2002

Tissue content of hydroxyestrogens in relation to survival of breast cancer patients.

PURPOSE: The main goal of our study was to assess estrogen contents of breast tumor tissues, having different estrogen receptor status, in relation to long-term follow-up of patients. EXPERIMENTAL DESIGN: Twenty-one breast cancer cases, all collected from January 1986 to January 1988 at the M. Ascoli Cancer Hospital Centre in Palermo, were included in the study and compared with 6 healthy women as a control group. Average follow-up time of patients was 144 +/- 10 months. The estrogen receptor status of tissues was determined by both ligand binding and immunohistochemical assays. A high performance liquid chromatography-based approach, jointly with gas chromatography/mass spectrometry, was used to identify and measure main estrogens, various hydroxyestrogens, and their methoxy derivatives in both normal and tumor tissues. RESULTS: Although variable concentrations of hydroxylated estrogens were detected, they consistently accounted for >80% of all of the estrogens. Significantly greater amounts of both 2- and 4-hydroxyestradiol, along with a marked increase of 16 alpha-hydroxyestrone (OHE(1)), were observed in cancer with respect to normal breast tissues. A significant positive association was observed with elevated 16 alpha OHE(1) (P = 0.015) in patients alive, leading to significantly lower (P = 0.043) 2OHE(1):16 alpha OHE(1) ratio values. Conversely, ratio values of 4:2 hydroxy+methoxy estrogens was significantly lower (P = 0.006) in deceased patients. Using cutoff values of 1.2 for 4:2 hydroxy+methoxy ratio and 150 fmol/mg tissue for 16 alpha OHE(1) we achieved a clear-cut separation of patients, with over-cutoff patients having 147 months and under cutoff patients showing only 47 months median survival time (P = 0.00008). CONCLUSIONS: Our data imply that individual hydroxyestrogens may have a distinct role in the onset and the clinical progression of breast cancer, with greater 16 alpha OHE(1) levels being in turn associated to cancer with respect to normal tissues and to a prolonged survival of breast cancer patients.

Adult↗
PubMed2003

Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: It has been proposed that physiologic levels of estrogens stimulate immune responses whereas androgens suppress inflammatory reactions. Thus, prevalence of synovial androgens relative to estrogens would be favorable in rheumatoid arthritis (RA). We investigated synovial fluid (SF) concentrations of several estrogens and androgens and conversion products of the sex steroid precursor dehydroepiandrosterone (DHEA) in supernatants of mixed synoviocytes. METHODS: SF steroid concentrations were measured by high performance liquid chromotography and mass spectrometry in 12 patients with RA and 8 subjects with traumatic knee injury (noninflammatory controls). Conversion of DHEA to downstream hormones was measured by thin-layer chromatography and phosphorimaging detection in 3 patients with RA and 3 patients with osteoarthritis (OA). RESULTS: Overall, SF concentration of free estrogens tended to be higher in RA patients versus controls (p < 0.06). Molar ratio of free SF estrogens/free SF androgens was elevated in RA compared to controls (1.17 +/- 0.32 vs 0.29 +/- 0.08, without unit; p = 0.017). The free SF concentration of the precursor androstenedione was significantly higher in RA patients than in controls (104.6 +/- 32.6 vs 30.4 +/- 0.4 ng/ml; p = 0.011), and SF estrone the aromatase conversion product of androstenedione was also elevated in RA compared to controls (13.6 +/- 2.6 vs 6.6 +/- 0.8 ng/ml; p = 0.035). The biologically active estrogen derivatives, 16a-hydroxyestrone and 4-hydroxyestradiol, were both higher in RA compared to controls (p = 0.085 and p = 0.044, respectively). In mixed RA synoviocytes, DHEA conversion yielded high local levels of 17beta-estradiol (708 pmol/l = 0.193 ng/ml) compared to testosterone (88 pmol/l = 0.026 ng/ml). CONCLUSION: SF levels of estrogens relative to androgens are significantly elevated, while those of androgens are markedly reduced, in patients with RA compared to controls. This imbalance is most probably due to increased aromatase activity. Thus, an available steroid precursor, such as DHEA, may be rapidly converted to proinflammatory estrogens in the synovial tissue, which may in turn stimulate the inflammatory process in patients with RA.

Adjuvants, Immunologic↗
PubMed1987

[Mechanism of the suppressive effect of catechol estrogen on the preovulatory LH surge].

The administration of 100 micrograms 2-hydroxyestrone (2-OHE1) or 2-hydroxyestradiol-17 beta (2-OHE2) at 0900h or 1000h in the morning of proestrus into normal 4-day cycling rats results in suppression of the preovulatory LH surge in the afternoon of that day. The LH-RH content of the median eminence in control rats decreases sharply in the afternoon from elevated noon levels. However, the catechol estrogen-treated rats do not show this decrease. These results indicate that the catecholestrogens block the preovulatory LH surge by preventing the release of LH-RH from the median eminence, but do not interfere with the synthesis and accumulation of LH-RH. Furthermore, injections of non-uterotropic 2-OHE1 twice at 30 minutes intervals into ovariectomized rats fail to affect the LH tonic secretion by 180 minutes after the initial injection. These data indicate that catechol estrogen interferes with the brief neuronal triggering phase necessary for LH-RH release, but does not affect the LH tonic secretion which is an estrogen-independent process.

Animals↗
PubMed1986

[Study on the central action of catecholestrogen: effect of 2-hydroxyestrogens on the preovulatory LH surge].

Administration of 100 micrograms 2-hydroxyestrone (2-OHE1) on the morning of proestrus to 4 day cycling rats resulted in suppression of the preovulatory LH surge. The greatest response was observed when the injection of 2-OHE1 coincided with plasma estradiol levels that were close to but not at their maximal proestrus levels. Injection of 100 micrograms 2-hydroxyestradiol-17 beta (2-OHE2-17 beta) effectively inhibited the LH surge when given at 0800 or 0900h, but not when injected at 1000 or 1200h. Non estrogenic 2-hydroxyestradiol-17 alpha was effective in suppressing the LH surge when given at 0900 or 1000h. Neither 2-OHE1 nor 2-OHE2-17 beta interfered with LH secretion in response to LH-RH administration, indicating that the inhibitory action of the catecholestrogen is exercised at the hypothalamic level. However, 2-OHE1 given five times following the implantation of an estradiol capsule in ovariectomized rats had no effect on the LH surge elicited on the second day. These data indicate that catecholestrogen interferes with the brief neuronal triggering phase necessary for LH-RH release, but not the sensitization phase of positive feedback of estrogen on phasic LH secretion. The evidence also indicates that the action does not involve conventional competition for the estradiol receptor.

Animals↗
PubMed1987

Anti-oestrogen antibodies in users of oral contraceptives and in patients with systemic lupus erythematosus.

Recent studies have demonstrated that many patients with SLE have elevated plasma levels of the minor oestrogen metabolite 16 alpha-hydroxyestrone (16 alpha OHE). This oestrogen is unique in its ability to react with lysine residues and form stable, covalent Heyns products with proteins. Increased levels of 16 alpha OHE-modified proteins have been found to occur on the membranes of red cells and lymphocytes in patients with SLE. In the present study, patient and control sera were analysed for the presence of circulating immunoglobulins which react with an oestrogen hapten. Anti-oestrogen antibodies were detected in 26% (9/34) of male and female SLE patients, and were found to correlate both with levels of plasma 16 alpha OHE (P less than 0.001) and with the presence of active disease (P less than 0.005). Surprisingly, this antibody activity was also observed in 25% (13/52) of normal, disease-free women who had a history of oral contraceptive use. No detectable activity was observed in normal men, women who had not taken oral contraceptives, or patients with a variety of other immunological diseases. The possible role of anti-oestrogen antibodies in both the hormonal exacerbation of SLE and in the long-term sequelae of oral contraceptive usage is discussed.

Adult↗
PubMed1977

Introduction of a 16 alpha-hydroxyl function into estrone by Streptomyces roseochromogenes.

Streptomyces roseochromogenes (NRRL B-1233) converted estrone predominantly into its 16 alpha-hydroxyl derivative. Chemical and spectroscopic (UV, IR, NMR, MS) methods were used in establishing the structure and strereochemistry of the oxidation product. The product was assigned as 16 alpha-hydroxyestrone (yield, 17%). No other oxidation product was detected in this experiment. An interrelationship between cell growth and 16 alpha-hydroxy-estrone formation was observed. Also, 16 alpha-hydroxylation of estrone was observed in resting cells. 16 alpha-Hydroxylase showed good activity at 3.7 X 10(-4)M of estrone concentration and was completely inhibited by 1.1 X 10(-3)M. These results indicate the presence of a constitutive 16 alpha-hydroxylase in the organism investigated.

Chemical Phenomena↗
PubMed1980

Response of serum prolactin to catechol estrogen in the immature rat.

The response of serum prolactin to the catechol estrogens, 2-hydroxyestrone (2-OH E1) and 2-hydroxyestradiol (2-OH E2) and their primary estrogens, estrone (E1) and estradiol (E2), was studied in 35-day-old male rats. The subcutaneous administration of 50 microgram of 2-OH E1 or 2-OH E2 significantly suppressed serum prolactin concentrations, but they were not significantly altered by the administration of 50 microgram of E1 or E2.

Animals↗
PubMed1989

Identification of oestrogen metabolites in human urine by capillary gas chromatography and mass spectrometry.

Oestrogen metabolites from the urine of males and pregnant and non-pregnant females were enriched by a procedure involving column chromatography on adsorber resins, gels and ion exchangers, enzymatic solvolysis and extraction, thereby separating the oestrogens from most of the interfering material. After derivatization of the oestrogens as their trimethylsilyl ethers profiles were measured with a fused silica column and a flame ionization detector by gas chromatography. Using a combination of capillary gas chromatography and mass spectrometry approximately 50 oestrogen metabolites were detected in the human urine of males and females, of which 19 were unknown urine compounds. Not all could be identified definitely owing to the lack of reference material. Mass spectra of trimethylsilylated oestrogens with functional groups at position 11 (11-dehydroestradiol, 11-dehydroestrone and 11 beta-hydroxyestrone) were discussed in their common and discernible fragmentations.

Chromatography, Gas↗
PubMed1991

The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis.

Cancer of the genital tract is the final outcome of some infections with human papillomavirus (HPVs), and the most estrogen-sensitive cells are at greatest risk for the HPV-related cancers. Therefore we investigated relationships between HPVs and estrogen metabolism in cells of the genital tract. Increased conversion of estradiol to 16 alpha-hydroxyestrone, known to be a risk factor for cancer in some other estrogen-sensitive cells, was investigated in keratinocytes from the genital tract. Primary cells, particularly those explants from the transformation zone of the cervix, are able to 16 alpha-hydroxylate estradiol. Both cervical and foreskin cells immortalized with HPV-16 are greatly enhanced in the 16 alpha-hydroxylation of estradiol as compared with normal cells. We suggest a model whereby the combined action of 16 alpha-hydroxylation of estrogen and HPV work together to promote cell proliferation.

Aryl Hydrocarbon Hydroxylases↗
PubMed1990

Multiple pathways for the oxidative metabolism of estrogens in Syrian hamster and rabbit kidney.

Microsomal preparations from hamster kidney, a target tissue for the carcinogenic action of stilbene-type and steroidal estrogens, catalyze the oxidative metabolism of diethylstilbestrol (DES). The formation of the major metabolite Z,Z-dienestrol and of reactive intermediates capable of protein binding were mediated by enzyme activities requiring nicotinamide-adenine dinucleotide phosphate (reduced form-NADPH), cumene hydroperoxide, or arachidonic acid (ARA). In addition, hydroxylated DES metabolites were detected in NADPH-supplemented incubations. The NADPH-dependent oxidation of DES was inhibited by SKF 525A and metyrapone. Monooxygenase-catalyzed metabolism was apparently responsible for the majority of DES oxidation in microsomes from whole hamster kidneys in vitro and this activity is preferentially localized in the kidney cortex. However, ARA-dependent, i.e., prostaglandin H synthase (PHS) mediated oxidation of DES and of the catechol estrogen 2-hydroxyestrone was demonstrated as well in the medulla of both rabbit and hamster kidney. It is proposed that monooxygenase and PHS activities act in concert in the metabolic activation of carcinogenic estrogens. This appears to apply in particular to steroidal estrogens, since catechol estrogens formed by monooxygenases are further oxidized to reactive intermediates by PHS and other peroxidatic enzymes.

Animals↗
PubMed1983

Inhibition of dihydropteridine reductase by catechol estrogens.

Catechol estrogens, such as 2-hydroxyestriol, 2-hydroxyestradiol, and 2-hydroxyestrone, inhibit human liver dihydropteridine reductase noncompetitively with Ki values ranging from 1.5 to 4.6 X 10(-6)M. Catechol estrogens lose approximately half of their inhibitory potency if the C-2 hydroxyl groups are methylated. Thus, 2-methoxyestrogens have inhibitory potencies equivalent to those of their parent estrogens--estriol, estradiol, and estrone. Aromatization of ring B or stereoisomerism at C-17 does not affect the inhibitory potency of estrogens, although stereoisomerism at C-16 enhances the inhibitory potency of estriol. These results support the hypothesis that catechol estrogens may interfere with catecholamine metabolism by acting as inhibitors of enzymes involved in catecholamine metabolism, such as dihydropteridine reductase.

Dihydropteridine Reductase↗
PubMed1975

Microbial oxidation of dehydroepiandrosterone and related compounds.

The oxidation of dehydroepiandrosterone (DHEA), 4-androstene-3, 17-dione, and estrone with Streptomyces roseochromogenes NRRL B-1233 was studied. The oxidation products were isolated and identified as as 16alpha-hydroxy-DHEA, 16alpha-hydroxy-4-androstene-3,17-dione and 16alpha-hydroxyestrone. The yields of these three products were 85%, 41% and 18%, respectively. This indicates the substrate stereospecificity of 16alpha-hydroxylase of the organism. An interrelationship between cell growth and the formation of 16alpha-hydroxylated steroid was observed in any case. For formation of 16alpha-hydroxy-DHEA, 16alpha-hydroxylase showed good activity at DHEA concentration of 3.47 x 10(-4)M. In the case of DHEA, 16alpha-hydroxy-4-androstene-3,17-dione and 5-androstene-3beta, 16alpha, 17beta-triol were obtained after the yield of 16alpha-hydroxy-DHEA reached the maximum yield for about 30 hr. The oxidation pathway of DHEA is discussed.

Androstenedione↗
PubMed1997

Characterization of rabbit UDP-glucuronosyltransferase UGT1A7: tertiary amine glucuronidation is catalyzed by UGT1A7 and UGT1A4.

A rabbit liver UDP-glucuronosyltransferase cDNA that is related to human and rat UGT1A7 has been identified. The predicted amino acid sequence of the UGT1A7l displays 80% similarity to that encoded by human HP4 (UGT1A9), but 81% to that predicted for human UGT1A7 and 77% to the rat UGT1A7 (UGTA2). The exons encoding human UGT1A7 and rat UGTA2 are the seventh of the series of cassette exons that flank the 3' common exon series of the UGT1A locus. Southern blot analysis demonstrates that the exon sequence encoding UGT1A7l is part of a larger cluster of highly related genes. The UGT1A7l RNA is expressed in both neonatal and adult liver, and unlike rat UGT1A2 which is inducible with Ah receptor ligands such as polycyclic aromatic hydrocarbons, rabbit UGT1A7l is not regulated when animals are exposed to these inducers. Following expression of UGT1A7l in COS-1 cells, glucuronidation activity was identified for small phenolic molecules like 4-nitrophenol, bulky phenols as represented by 4-hydroxybiphenol and octylgallate, as well as 4-hydroxyestrone. In addition, UGT1A7l possesses catalytic activity toward tertiary amines like the tricyclic antidepressant imipramine. The pattern of UGT1A7l glucuronidation is similar to that observed for human UGT1A9, except tertiary amines are not subject to glucuronidation by human UGT1A9. Glucuronidation of tertiary amines is catalyzed principally by human UGT1A4 as well as rabbit UGT1A4. Although rabbit UGT1A7l catalyzes the formation of quarternary ammonium glucuronides, the Vmax is considerably less than that observed for rabbit UGT1A4. Overall, the characterization of rabbit UGT1A7l suggests that this protein represents the ortholog of the human UGT1A7, which to date has not been identified.

Amines↗
PubMed1997

Release of iron from ferritin storage by redox cycling of stilbene and steroid estrogen metabolites: a mechanism of induction of free radical damage by estrogen.

Estrogens induce hydroxyl radical-mediated DNA and protein damage and lipid peroxidation. As part of a study of the mechanism of hydroxyl radical generation by estrogens, we investigated the in vitro mobilization of Fe2+ from ferritin by redox cycling of the stilbene or steroid estrogen metabolites diethylstilbestrol-4',4"-quinone (DESQ), equilenin-3,4-quinone (EQ), or estrone-3,4-quinone (3,4EQ). Aerobic cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ increased the reduction of succinoylated cytochrome c, a measure of superoxide radical formation, by 19-20% over control values (24.5+/-0.3 microM) in the absence of estrogen quinone substrate. Rates of Fe2+ release from horse spleen ferritin by cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ were 94.4+/-0.6, 117.2+/-9.4, or 137.7+/-19.9 pmol Fe2+/min, respectively, compared to 67.3 + 2.3 pmol Fe2+/min in the absence of estrogen substrates. Redox cycling of 35.5 microM DESQ, EQ, or 3,4EQ mediated by microsomes of hamster kidney, a target organ of estrogen-induced carcinogenesis, released 511+/-30.10, 516.91+/-22.90, or 410.27+/-28.49 pmol Fe2+/min, respectively. Corresponding values with microsomes of hamster liver, where tumors do not develop by estrogen treatment, were 272.27+/-43.10, 222.25+/-21.78, or 91.36+/-8.54 pmol Fe2-/min, respectively. Diethylstilbestrol, equilenin, and 4-hydroxyestrone do not induce detectable iron release from ferritin under these conditions. The cytochrome P450 reductase-mediated redox cycling of DESQ, EQ, or 3,4EQ in the presence of iron resulted in the hydroxylation of benzoic acid by hydroxyl radical attack. These data demonstrate that redox cycling of estrogen metabolites releases Fe2+ from ferritin, which in turn generates hydroxyl radicals by a Fenton reaction. This estrogen-induced hydroxyl radical damage may contribute to tumor initiation in hormone target tissues, including breast cancer.

Animals↗
PubMed1993

cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily.

Two new UDP-glucuronosyltransferase cDNAs, designated UGT2B10 and UGT2B11, encoding 528 amino acid proteins were isolated from a human liver cDNA library. The deduced amino acid sequences of UGTs 2B10 and 2B11 share > 76% sequence similarity with other known human liver UGT2B subfamily isoforms and < 48% sequence similarity with UGT1 family proteins. COS-7 cells transfected with UGT 2B10 and 2B11 synthesized proteins with respective molecular masses of 49kDa and 51kDa. UGT2B11 expressed in COS-7 cells glucuronidated a number of polyhydroxylated estrogens (estriol, 4-hydroxyestrone and 2-hydroxyestriol) and xenobiotics (4-methylumbelliferone, 1-naphthol, 4-nitrophenol, 2-aminophenol, 4-hydroxybiphenyl and menthol). Despite the screening of more than forty potential substrates, glucuronidation activity was not observed for expressed UGT2B10.

Amino Acid Sequence↗
PubMed1996

cDNA cloning and characterization of the human UDP glucuronosyltransferase, UGT1A3.

The cDNA encoding the UDP glucuronosyltransferase, UGT1A3, has been cloned and expressed in cell culture. The deduced amino acid sequence of the cDNA is 90% similar in sequence to that of a previously characterized form, UGT1A4 and to that of a third form, UGT1A5 whose function in unknown. UGT1A3, when expressed in COS cells has a relative molecular mass of 55 kDa and is active in the glucuronidation of estrone and 2-hydroxyestrone. Activity towards other polyhydroxylated estrogens including 4-hydroxyestrogen and estriol and its metabolites was not detected. UGT1A3 was also inactive towards androgens and their metabolites. The enzyme preferentially glucuronidated the N-hydroxy metabolite of 2-acetylaminofluorence and was more active towards the 6- and 12-hydroxylated metabolites of benzo[alpha]pyrene. RNA encoding UGT1A3 was detected in human liver and colon tissue.

Animals↗
PubMed1997

The effects of the phosphorothioate insecticide fenitrothion on mammalian cytochrome P450-dependent metabolism of estradiol.

Phosphorothioate insecticides, such as fenitrothion, are suicide substrates of cytochromes P450 (P450). These compounds undergo oxidative desulfuration by P450 resulting in the release and subsequent binding of atomic sulfur to the enzyme. Consequently, the P450-dependent metabolism of certain endogenous substrates could be inhibited by exposure to these insecticides. Formation of 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 16 alpha-hydroxyestrone (16 alpha-OHE1), and estriol in mammals occurs by P450-dependent hydroxylation of estradiol at various positions on the steroid nucleus. In the present study, pretreatment of male Swiss Webster mice with increasing doses of fenitrothion resulted in dose-dependent biphasic decreases in 2-OHE2 and 4-OHE2 production in mouse hepatic microsomes compared to control, with substantial decreases even at a dosage as low as 7 mg/kg. Fenitrothion pretreatment also resulted in dose-dependent biphasic increases in 16 alpha-OHE1 and estriol production, along with substantial increases in estrone formation, probably as a result of shunting from the inhibition of 2- and 4-hydroxylation. These data suggest that exposure to fenitrothion might alter estradiol metabolism by inhibition of certain P450 isozymes.

Animals↗
PubMed1993

Experimental down-regulation of intermediate biomarkers of carcinogenesis in mouse mammary epithelial cells.

The polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA) is a metabolism-dependent procarcinogen whose tumorigenicity is modified by dietary and endocrine manipulations in vivo. DMBA initiates molecular and cellular alterations in the mammary tissue, while dietary components and estrogens affect the post-initiational phase of tumorigenic transformation. The mechanism(s) responsible for modulation of tumorigenic transformation remain unclear. This study examines the effects of selected tumor suppressing agents and estradiol (E2) metabolites on in vitro DMBA carcinogenesis utilizing a newly established mouse mammary epithelial cell line C57/MG. Alteration in DNA repair synthesis, metabolism of E2 via the C2- and C16 alpha-hydroxylation pathways, and acquisition of anchorage-independent growth were utilized as molecular, endocrine, and cellular biomarkers to quantitate the cellular transformation by DMBA and its modulation by tumor suppressing agents and E2 metabolites. A single 24 hr exposure of 0.78 microM DMBA to C57/MG cells resulted in a 193.9% increase in DNA repair synthesis and a 73.1% decrease in C2/C16 alpha hydroxylation of E2. The DMBA treated C57/MG cells also exhibited increased anchorage-independence in vitro prior to tumorigenesis in vivo. A simultaneous treatment of cells with DMBA and with the highest noncytotoxic doses of the tumor suppressing agents 5 microM N-(4-hydroxyphenyl) retinamide (HPR), 50 microM indole-3-carbinol (I3C), or 1 microM tamoxifen (TAM) resulted in a 35.6% to 63.9% decrease in DNA repair synthesis, a 23.8% to 1347.6% increase in C2/C16 alpha hydroxylation of E2, and a 53.8% to 72.4% decrease in anchorage-independent growth. The E2 metabolites at the highest non-cytotoxic doses of 0.76 microM estrone (E1), 0.69 microM 2-hydroxyestrone (2-OHE1), and 0.66 microM 2-methoxyestrone (2-MeOHE1) suppressed DMBA-induced DNA repair synthesis by 56.0% to 68.8%. These tumor suppressing agents and E2 metabolites also effectively suppressed post-initiational, anchorage-independent growth by 24.9% to 72.4%. These results indicate that DMBA induces cellular transformation in part by causing DNA damage, altering C2/C16 alpha hydroxylation in favor of C16 alpha-hydroxylation, and inducing anchorage-independent growth prior to tumor development. Effective downregulation of these genotoxic, endocrine and proliferative end points by prototypic tumor suppressing agents and by E2 metabolites generated via the C2-hydroxylation pathway suggest that these agents may influence mammary tumorigenesis by inhibiting early occurring initiational and/or post initiational events.

9,10-Dimethyl-1,2-benzanthracene↗