Effects of Environmental Chemicals on Drug-Metabolizing Enzymes

Goldstein, J A.

Abstract

The objectives of this study are to examine changes in subspecies of cytochrome P-450c and P-450d in the rat after treatment with environmental chemicals and to assess the implications of these changes. 1. Induction by a PCB Isomer: Dose response curves and time courses indicate that P-450d are coordinately induced by 3,4,5,3',4',5'-HCB. 2. Methylenedioxyphenyl compounds (MDO) which act as suicide substrates induce different P-450 isozymes. They also differ in their ability to form complexes with different isozymes. Coadministration of methylcholanthrene with MDOs represses induction of P-450b by MDOs at the level of mRNA. 3. Structure-activity relationships of chlorobenzenes as inducers was studied. Hexachlorobenzene is the only 3-MC type inducer. 4. Two constitutive isozymes have been isolated P-450H and P-450G and antibodies raised to these forms. The goal of this project is to better understand the changes occurring in metabolic capability of the liver toward chemical after exposure to environmental chemicals. Antibodies and cDNAs developed to these cytochromes will be used in studying these effects.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES021024-04
• Application #: 4693155
• Support Year: 4
• Fiscal Year: 1985

Institution

• Name: U.S. National Inst of Environ Hlth Scis
• Country: United States

Publications

Makia, Ngome L; Goldstein, Joyce A (2016) CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor ? in Human Liver. Mol Pharmacol 89:154-64

Langaee, Taimour Y; Zhu, Hao-Jie; Wang, Xinwen et al. (2014) The influence of the CYP2C19*10 allele on clopidogrel activation and CYP2C19*2 genotyping. Pharmacogenet Genomics 24:381-6

Shi, Zhe; Yang, Wenjun; Goldstein, Joyce A et al. (2014) Med25 is required for estrogen receptor alpha (ER?)-mediated regulation of human CYP2C9 expression. Biochem Pharmacol 90:425-31

Makia, Ngome L; Surapureddi, Sailesh; Monostory, Katalin et al. (2014) Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping. Mol Pharmacol 86:125-37

Chen, Yuping; Coulter, Sherry; Jetten, Anton M et al. (2009) Identification of human CYP2C8 as a retinoid-related orphan nuclear receptor target gene. J Pharmacol Exp Ther 329:192-201

Delozier, Tracy C; Kissling, Grace E; Coulter, Sherry J et al. (2007) Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues. Drug Metab Dispos 35:682-8

Lee, Su-Jun; van der Heiden, Ilse P; Goldstein, Joyce A et al. (2007) A new CYP3A5 variant, CYP3A5*11, is shown to be defective in nifedipine metabolism in a recombinant cDNA expression system. Drug Metab Dispos 35:67-71

Lee, Su-Jun; Perera, Lalith; Coulter, Sherry J et al. (2007) The discovery of new coding alleles of human CYP26A1 that are potentially defective in the metabolism of all-trans retinoic acid and their assessment in a recombinant cDNA expression system. Pharmacogenet Genomics 17:169-80

Parikh, S; Ouedraogo, J-B; Goldstein, J A et al. (2007) Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 82:197-203

Vyas, Piyush M; Roychowdhury, Sanjoy; Khan, Farah D et al. (2006) Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: I. Expression and role of cytochromes P450. J Pharmacol Exp Ther 319:488-96