Hydroxy-3-methylcholanthrenes

Hydroxy-3 -hydroxy-methylcholanthrene (1-OH-3-OHMC), 3 -methylcholanthrene (3MC), trans- and c s-l,2-diols and l-hydroxy-3-methylcholanthrene (1-OH-3MC) (R)-N-(3,5- dinitroberrzoyl)- phenylglycine (Pirkle-type) CSP 21... 

Methylcholanthrene (3-MC) is a potent carcinogen, intermediate in activity between DMBA and BP (27,77). It was first prepared in 1925 by Wieland from desoxycholic acid (89). Biological studies have tentatively identified the 9,10-dihydrodiol (24a) and/or its 1- or 2-hydroxy derivatives (24b and 24c) and the corresponding diol and triol epoxides (25 -c) as the proximate and ultimate carcinogenic forms, respectively, of 3-MC (90-93). 

Recently, the mechanism of 6-nitro-BaP ring hydroxylation has been elucidated by using 3-deutero-6-nitro-BaP (144). When incubated with 3-methylcholanthrene-induced rat liver microsomes, this deuterated analogue yielded the same metabolite profile previously observed with 6-nitro-BaP. Spectroscopic analysis of 3-hydroxy-6-nitro-BaP and 6-nitro-BaP-3,9-hydroquinone indicated that 30% of the deuterium label had migrated to carbon 2, presumably via an NIH shift. Therefore, it appears that 6-nitro-BaP-2,3-oxide is a common intermediate for these two metabolites. 

Treatment of immature male rats with phenobarbital for three days increased the 6 ft-, la-, and 16a-hydroxyl ati on of testosterone by liver microsomes to different degrees (36). The 16a-hydroxyl ati on reaction was stimulated several-fold, whereas the 6ft- and 7a-hydroxylations were stimulated to a smaller extent. In contrast to these results, the administration of 3-methylcholanthrene had little or no stimulatory effect on the 6ft- or 16a-hydroxylation of testosterone by liver microsomes but caused a significant increase in the 7 a-hydroxy 1 ati on reaction. 

Pb, phenobarbital BHT, butylated hydroxy toluene 3-MC, 3-methylcholanthrene TCDD, 2,3,7,8-tetrachlorodibenzdioxin PCBs, polychlorinated biphenyls. 

Abbreviations are as in Table I and DMBA 7,12-dlmethylbenz-anthracene TPA = 12-0-tetradecanoylphorbol-13-acetate BBN = butyl(4-hydroxy)butyl-nitrosamlne FANFT = N-[4-(5-nltro-2-furyl)-2-thiazolyl] formamlde SMC = 3-methylcholanthrene MNNG = N-methyl-N -nltro-N-nitrosoguanidlne. 

The metabolism of ochratoxin A was studied in cultured rat and human primary hepatocytes incubated with non-cytotoxic concentrations of PH]ochratoxin A ranging from 10 to 10 mol/l for 8 h. In rat hepatocytes, ochratoxin A was metabolized to small amounts of three products. In addition to 4-hydroxy-ochratoxin A, which is a known product of ochratoxin A biotransformation, two novel metabolites were detected and tentatively identified as hexose and pentose conjugates of ochratoxin A. In vitro induction with 3-methylcholanthrene increased the formation of 4-hydroxy-ochratoxin A but did not alter the formation of the conjugated metabolites (Gross-Steinmeyer et al., 2002). 

In the apparently major pathway for the conversion of cholesterol into 5 -cholestane-3a,7a,12a-triol, the step following the formation of 7a-hydroxy-4-cholesten-3-one is a 12a-hydroxylation yielding 7a,12a-dihydroxy-4-cholesten-3-one (Fig. 1). The reaction is catalyzed by the microsomal fraction fortified with NADPH (15,37). The conversion of 5-cholestene-3, 7a-diol into 5-cholestene-3/5,7a,12a-triol, which is a reaction in another pathway for the formation of 5/5-cholestane-3a,7a,12a-triol, is also catalyzed by the microsomal fraction fortified with NADPH (30,37), as is the 12a-hydroxylation of 5/5-cholestane-3a,7a-diol and 7a-hydroxy-5)5-cholestan-3-one (37). The rates of 12a-hydroxylation of these C27-steroids differ considerably the rate with 5-cholestene-3/5,7a-diol is about one-tenth and with 5 -cholestane-3a,7a-diol about half of that with 7a-hydroxy-4-cholesten-3-one (37). Einarsson (37) and Suzuki et al. (38) have studied some properties of the 12a-hydroxylase system with special reference to the possible participation of electron carriers such as NADPH-cytochrome c reductase and cytochrome P-450. The 12a-hydroxylation of 7a-hydroxy-4-cholesten-3-one was inhibited by cytochrome c, indicating that NADPH-cytochrome c reductase might be involved. However, no direct evidence for the participation of flavins was obtained. If NADPH-cytochrome c reductase participates, it is not rate-limiting, since the activity of this enzyme increases upon treatment with thyroxine whereas the activity of the 12a-hydroxylase decreases (39). Suzuki et al. (38) found no inhibition of 12a-hydroxylation by carbon monoxide, whereas Einarsson (37) obtained some inhibition. The 12a-hydroxylase activity was unaffected by methylcholanthrene treatment (40) and lowered by phenobarbital treatment (37,38). These observations indicate that the cytochrome(s) P-450 induced by methylcholanthrene and... 

The effects of cysteine pretreatment on hepatic microsomal demethylation of DMN and deethylation of diethylnitrosamine (DEN) were compared (34J). While cysteine inhibited DMN demethylase, no inhibitory effect on the production of acetaldehyde from DEN was observed. The hepatic deethylation of DEN was stimulated by pretreatment of rats with phenobarbitone, 3-methylcholanthrene, butylated hydroxy toluene, and DDT (318). The hepatic DEN deethylase activity in mice has been determined as a function of age and sex (389a). Peak activity was reached in both sexes between the seventh and fifteenth days of life thereafter, activity was higher in males. Mice treated with DEN at day 15 in carcinogenesis assays showed a higher incidence of liver tumors than those treated later, but no sex difference was observed in these experiments. 

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