PMID- 2507189
OWN - NLM
STAT- MEDLINE
DCOM- 19891113
LR  - 20190510
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 10
IP  - 10
DP  - 1989 Oct
TI  - Epoxide hydratase: sex specific expression and rate-limiting role in DMBA 
      metabolism.
PG  - 1883-90
AB  - The rate of generation of the proximate carcinogen 7,12-dimethylbenz[a]anthracene 
      3,4-dihydrodiol (DMBA 3,4-diol) from DMBA, was 3-fold lower in rat liver 
      microsomes (RLM) from female, compared to male Sprague-Dawley rats. However, the 
      sum of products that potentially derive from the common intermediate DMBA 
      3,4-oxide namely, DMBA 3,4-diol, 3- and 4-hydroxy DMBA, was comparable between 
      the two sexes (18 versus 20 pmol/mg/min). Addition of purified microsomal epoxide 
      hydratase (EHm) (150 nM) to female RLM increased the rate of DMBA 3,4-diol 
      formation to a level comparable to that obtained in male RLM. This activity was 
      not increased when equivalent amounts of EHm were added to male RLM. Female RLM 
      contained 2-fold lower levels of EHm protein compared to male RLM, based on 
      Western blot analyses, and exhibited correspondingly lower hydrating activities 
      towards both benzo[a]pyrene 4,5-oxide (BP 4,5-oxide) and DMBA 5,6-oxide. The rate 
      of DMBA 3,4-diol formation was also limited by the availability of EHm in lung 
      and adrenal microsomes from male rats. Addition of exogenous EHm to both tissues 
      stimulated DMBA 3,4-diol formation by 2 and 6-fold respectively. EHm activity was 
      still more deficient in the formation of the K-region, DMBA 5,6-diol, and this 
      limitation was seen in both female and male-RLM as well as in microsomes from 
      extrahepatic tissues. These limiting effects were enhanced by 
      3-methylcholanthrene treatment, through increases in DMBA monooxygenase but not 
      EHm activities, but were diminished by phenobarbital treatment where EHm was also 
      induced. Manipulation of EHm activity (through addition of pure EHm or its 
      inhibitor trichloropropylene oxide) demonstrated a direct relationship between 
      EHm activity and total DMBA metabolism. A deficiency in EHm apparently caused a 
      selective loss of products resulting from initial DMBA 5,6- and 
      8,9-monooxygenation. Substantial reduction of DMBA 5,6-oxide to DMBA was measured 
      in RLM under anaerobic conditions. This reduction was inhibitable by ambient 
      oxygen levels. These data indicate that insufficient cellular EHm levels result 
      in the reversion of microsomally generated DMBA 5,6-oxide (and 8,9-oxide) back to 
      DMBA and also lead to reduced activation of DMBA via the carcinogenic bay region 
      diol epoxide.
FAU - Christou, M
AU  - Christou M
AD  - Department of Pharmacology, University of Wisconsin Medical School, Madison 
      53706.
FAU - Jovanovich, M C
AU  - Jovanovich MC
FAU - Jefcoate, C R
AU  - Jefcoate CR
LA  - eng
GR  - CA 16265/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 57-97-6 (9,10-Dimethyl-1,2-benzanthracene)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - 9,10-Dimethyl-1,2-benzanthracene/*metabolism
MH  - Animals
MH  - Epoxide Hydrolases/*metabolism
MH  - Female
MH  - Kinetics
MH  - Male
MH  - Microsomes, Liver/drug effects/*enzymology
MH  - Phenobarbital/pharmacology
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Sex Factors
EDAT- 1989/10/01 00:00
MHDA- 1989/10/01 00:01
CRDT- 1989/10/01 00:00
PHST- 1989/10/01 00:00 [pubmed]
PHST- 1989/10/01 00:01 [medline]
PHST- 1989/10/01 00:00 [entrez]
AID - 10.1093/carcin/10.10.1883 [doi]
PST - ppublish
SO  - Carcinogenesis. 1989 Oct;10(10):1883-90. doi: 10.1093/carcin/10.10.1883.