A Practical Approach, Second Edition=Ronald D. Ho.pdf

ROLE OF XENOBIOTIC METABOLISM IN DEVELOPMENTAL AND REPRODUCTIVE TOXICITY 539In animals, a significant increase in maternal liver weight during pregnancy is noted and is aresult of the proliferation of parenchymal cells. 54,60 This increases microsomal yield per liver. 54However, according to Combes et al., 61 one should keep in mind that the liver is not enlarged duringpregnancy in humans. Several reports describe changes in the rates of hepatic microsomal P450-mediated xenobiotic oxidation during pregnancy. 54,55,62–65 For example, in the mouse, the declinesin specific activity for N-demethylation of carbaryl and nicotine were 20% and 50%, respectively,on day 12 of gestation, and remained statistically lower on GD 18. 54 Similarly, the rates of 7-ethoxycoumarin O-dealkylase (ECOD) decreased 11% and 39% on GD 12 and 18, respectively. 54A report 64 suggested no pregnancy-related change in the N,N-dimethylaniline demethylase activityin mouse hepatic microsomes while aminopyrine N-demethylase showed a modest decline. Therates of dearylation of EPN, but not parathion, declined significantly by day 12 of pregnancy butreturned to nonpregnant levels by day 18. 54 Hepatic aldrin epoxidase activity continued to declinetoward term 54,65 but posted no change in total capacity. Parathion undergoes dearylation and desulfurationcatalyzed by hepatic P450. Although the dearylation of parathion exhibited no changein the rate, a 51% decline was noted in desulfurase activity in mouse liver during pregnancy. 66 Ourobservations suggest 54,64,65 that the total capacity of liver for dealkylation of nicotine, carbaryl,aminopyrine, N,N-dimethylaniline, and 7-ethoxycoumarin, and epoxidation of aldrin does notchange as result of pregnancy. Similar observations have been noted for parathion. 54,67b. InductionIn pregnant golden hamsters, ethanol treatment resulted in a 50% increase in CYP2E protein. 56Treatment of pregnant mice with polychlorinated biphenyls (PCBs) significantly increased thedimethylnitrosamine demethylase activity. 63 Pretreatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on GD 10 has been reported to cause an approximate 15-fold inductionof maternal liver AHH on GD 20. 62 Cytochrome P450 IIIA1, which is normally undetectable inthe maternal liver, was significantly elevated at GD 15 to 21 following pregnenolone-16-carbonitrile(PCN) exposure of pregnant rats. 68Many reports have described the effect of chemical pretreatment of pregnant animals on theteratogenicity of test chemicals. Qualitative and quantitative changes in P450s were believed to beresponsible for the observed results. Cyclophosphamide teratogenicity depends on its bioconversionto phosphoramide mustard and/or acrolein. Rodent embryos are incapable of this activation andrequire supplementation with adult liver S 9 fraction as an activation system in the culture medium.More effective activation was noted with a liver S 9 fraction prepared from adult male rats pretreatedwith phenobarbital or a mixture of PCBs other than that from untreated or 3-methylcholanthrene(3-MC) pretreated rats. 69,70 In contrast to these results, an S 9 fraction prepared from adult male ratspretreated with either 3-MC, Aroclor 1254, or isosafrole, but not from phenobarbital or PCN, wasfound to be more effective in enhancing 2-acetylaminofluorene (AAF) dysmorphogenesis in ratembryos. 70,71 The required P450s are not induced in the maternal liver by pretreatment of rats with3-MC, Aroclor 1254, isosafrole, phenobarbital, or PCN. Transplacental exposure of GD 8 embryosto 3-MC resulted in a high percentage of malformed embryos following explantation on GD 10 ina medium containing AAF. 70,71For several reasons, the approach of using inducers in studies of chemical teratogenicity isseriously flawed, and considerable caution should be exercised in the interpretation of results ofsuch models. Under in vivo conditions, it is difficult to identify the enzyme responsible forbioactivation of the test chemical. For example, cyclophosphamide oxidation is not only mediatedby P450, but also by PGS 72 and LO, 73 and various chemicals also induce LOs. 29,30 The P450 inducers3-MC, BP, or phenobarbital are themselves teratogenic and thus may weaken and predisposeembryos to the teratogenicity of a test agent. Thus, the observed exaggerated response may not bedue to the test agent alone but may reflect a potentiative or synergistic interaction between inducerand test chemical. Furthermore, the residues of inducers and/or their toxic metabolites occur as© 2006 by Taylor & Francis Group, LLC