Carcinogens Methylcholanthrene

Methylcholanthrene [56-49-5] M 268.4, m 179-180 . Crystd from benzene and diethyl ether. CARCINOGEN. 

Cerniglia CE, RH Dodge, DT Gibson (1982d) Fungal oxidation of 3-methylcholanthrene formation of proximate carcinogenic metabolites of 3-methylcholanthrene. Chem-Biol Interactions 38 161-173. 

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

Although benz(a)anthracene (BA) is generally considered noncarcino-genic (27), it is a weak tumor initiator when administered with a phorbol ester promoter (28). More importantly, BA is a convenient model for the highly potent carcinogenic PAH 7,12-dimethylbenz(a)-anthracene and 3-methylcholanthrene (27), both of which are BA derivatives but which offer more serious synthetic problems. 

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). 

Multiple forms of cytochrome P-1+50. It is now clear that there are more than one form of cytochrome P-1+50. Thomas et al. have recently shown by immunochemical means that there are at least six forms of mammalian cytochrome P-1+50 (39) In 1960 s it was noted that there are at least two catalytically and spectrally distinct cytochrome P-l+50 s, viz. cytochrome P-1+50 and cytochrome P-1+1+8 or P -1+50 (1 0, 1 1). Cytochrome P-1+1+8 is inducible by PAH s such as 3-methylcholanthrene (MC) and BP. It metabolizes preferentially PAH s (such as the above carcinogenic inducers). Cytochrome P-1+1+8 derives its name from the fact that when reduced and complexed with carbon monoxide it has an absorbance maximum at 1+1+8 nm. Cytochrome P-1+50 induced by compounds such as phenobarbital (PB) appears similar to the control cytochrome P-1+50 both spectrally and catalytically. 

This type of induction is caused by a large group of environmental chemicals, both natural such as plant indoles and man made such as polycyclic hydrocarbons. Examples include benzo [a]pyrene, benzo[a]anthracene, 3-methylcholanthrene, p-napthoflavone, polychlorinated biphenyls and benzo-p-dioxins, and dibenzofurans. Many of these compounds are of interest as they are carcinogenic. 

N-hydroxylation is not the only or major route of metabolism in vivo, nor is it the only reaction catalyzed by the microsomal enzymes. Ring hydroxylation is the major route of metabolism, the products of which are not carcinogenic. These alternative routes of metabolism are inducible in vivo by pretreatment with agents such as phenobarbital and 3-methylcholanthrene (see chap. 5). 

Cytochromes P450 often convert drugs or other foreign compounds to forms that are more readily excreted.499 However, the result is not always beneficial. For example, 3-methylcholanthrene, a strong inducer of cytochrome P450, is converted to a powerful carcinogen by the hydroxylation reaction.500 See also Box 18-E. 

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