The effect of gender, sexual maturation and xenobiotic treatment on the formation of hydroxymethyl metabolites from 7,12-dimethylbenz[a]anthracene in rat liver microsomes

• Published in: Toxicology letters Vol. 117; no. 1; pp. 1 - 9
• Main Authors: Boyle, Susanne P., Craft, J.A.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 30.09.2000; Amsterdam Elsevier Science
• Subjects: 7,12-DMBA; 9,10-Dimethyl-1,2-benzanthracene - metabolism; Animals; Benzphetamine - metabolism; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; CYP2C11; Cytochrome P-450 Enzyme System - metabolism; Cytochromes P450; Female; Gender-specific; Hypophysectomy; Inorganic dusts (pneumoconiosises) and organic dusts (byssinosis etc.); Isoenzymes - metabolism; Male; Medical sciences; Methylation - drug effects; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Phenobarbital - pharmacology; Rats; Rats, Long-Evans; Sex Factors; Sexual Maturation; Toxicology; Tumors; Xenobiotics - pharmacology; 12OHMe7MBA, 12-hydroxymethyl-7-methylbenzanthracene; CYP2C11; 7OHMe12MBA, 7-hydroxymethyl-12-methylbenzanthracene; Hx, hypophysectomy; AUC, area under curve; GC–MS, gas chromatography–mass spectrometry; 7,12-DMBA; CYP, cytochrome P450; Cytochromes P450; Gender-specific; 7,12-DMBA, 7,12-dimethylbenz(a)anthracene; Rat; Isozyme; Toxicity; Liver; Sex; Microsome; Enzymatic activity; Pituitary gland; Pretreatment; Unspecific monooxygenase; Hydrocarbon; Hydroxylation; Regioselectivity; Enzyme; Cytochrome P450; Rodentia; Polycyclic aromatic compound; Metabolism; In vitro; Carcinogen; Pollutant; Vertebrata; Sexual maturity; Phenobarbital; Mammalia; Impuberal animal; Adult animal; Drug-metabolizing enzyme; Oxidoreductases
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/S0378-4274(00)00230-7

The effects of age, gender, strain, phenobarbital (PB) treatment and pituitary influence on the regioselective metabolism of 7,12-dimethylbenz[a]anthracene to hydroxmethyl metabolites were investigated. Studies used hepatic microsomal membranes from immature and mature Long Evans (LE) rats and adult Hooded Lister (HL) animals. Hydroxymethyl metabolites were resolved by both normal and reverse phase HPLC with on-line diode array detection. The CYP isoform(s) responsible for oxidation at the 12 methyl position exhibited no gender or developmental regulation and the rate of formation was not altered following hypophysectomy. PB-treatment of adult rats caused a significant increase in the rate of formation of both male and female animals (29 and 41-fold, respectively) suggesting a major contribution from a PB-inducible isoform, such as CYP2B. The rate of formation of 7OHMe12MBA exhibited no gender dependency in immature animals but was 2-fold greater than that observed for 12OHMe7MBA suggesting that steric hindrance resulting from the adjacent 1,2 benzyl ring favours substrate oxidation at the 7-methyl position. Male predominant formation of 7OHMe12MBA was apparent following sexual maturation of the LE rats and was significantly reduced upon hypophysectomy suggesting the involvement of a male-specific GH dependent isoform e.g. CYP2C11.