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HK0270082 35625 A SPECIFIC CARRIER FOR r)XYGEN A,~ID CARB(~R M0,'IOXIDE IN TIIE LUNG AND PLACENTA DRUG META~ DISPOS i(i): 374-379; 1973 BUR~JS, B/ GURTNER, GH/ MAN!ERING, HOLT~AN, GILLETTE, SHOE,'IAN, WILSOtl PURPOSE: IT IS POSSIBLE THAT THE CYTOCHROME DRUG-METABOLIZING ENZYMES MAY PLAY A HERETOFORE UNSUSPECTED ROLE IN GAS TRANSFER IN THE LUNG AND PLACENTA, SINCE CYTOCHROME P-450 Is PRESENT IN GREATEST AMOUNTS IN LUNGSs PLACENTAs AND LIVERs IT MAY POSSIBLY FACILITATE OR ASSIST IN THE TRANSFER OF OXYGEN (02) AND CARBON MONOXIDE (C0), WHICH BIHD TO ITs IN THESE LOCATIONS, THIS STUDY INVESTIGATED THE EXTENT TO WHICH VARIOUS SUBSTANCESs INCLUDING NICOTINE!, BENZO(A)PYRENEs SOME COMMONLY-USED DRUGS, AND SKF-525-A, A DRUG KNOWN TO BIND TO CYTOCHROME P-450 IN VlVO, INTERFERE WITH A SPECIFIC TRANSPORT MECHANISM FOR 02 AND CO IN THE LUNG AND PLACENTA OF DOGS AND/OR SHEEP, ~: LUNG DIFFUSING CAPACITY FOR CO WAS MEASURED USING A REBREATHING METHOD IN ANESTHETIZED MONGREL DOGS AND ADULT SHEEP BEFORE AND AFTER VENOUS INFUSION WITHIN 5 MIN OF THE DRUG TO BE TESTED, INCLUDING 500 MG NICOTINE OR 500 MG BP, PLACENTAL 02 TRANSFER WAS MEASURED IN TERM EWES VIA CANNULATION OF THE SEVERED UMBILICAL CORD, REPLACING THE FETUS WITH AN EXTERNAL RESERVOIR~ DEOXYGENATOR AND PERFUSION SYSTEM, TEST COMPOUNDS WERE INJECTED ALL AT ONCE INTO THE PERFURION CIRCUIT ON THE FETAL SIDE OF THE PLACENTA, THE PERFUSION FLUID WAS SATURATED WITH ARGONs AND 02 TRANSFER WAS MEASURED FROM MOTHER TO FETUS AND ARGON TRANSFER FROM FETUS TO MOTHER, FINDINGS: NICOTINE (500 MG) HAD NO EFFECT ON CO DIFFUSING C'iFi 98 COHG 0"1036

J HK0270083 35625 CAPACITIES IN THE DOG, WHILE CHLORPROMAZINE AND THE PLASTICIZER BIS-2-ETHYLHEXYL PHTHALATE DECREASED THEM. SKF-525-A INCREASED THE DIFFUSION RESISTANCE OF THE PULMONARY EXCHANGE MEMBRANE TO C0 IN SHEEP WHILE THE CAPILLARY VALUME REMAINED UNCHANGED. BP, NICOTINE SULFATE, DL-AMPHETAHINE, CHLORPROMAZINE, AND IMIPRA- MINE CAUSED A MUCH LARGER PERMEABILITY FOR ~9 THAN FOR ARGON ACROSS THE PLACENTA. OXYGEN TRANSPORT DECREASED WITH ALL DRUGS EXCEPT NICOTINE~ ADMINISTRATION OF NICOTINE WAS FOLLOWED BY A SLIGHT INCREASE IN 02 TRANSPORT. '%HE 02TRANSPORT SYSTEM MAY HELP TO EXPLAIN THE EFFECTS OF SMOKING AND NARCOTICS ADDICTION ON BIRTH WEIGHT IN HUMAN INFANTS, SINCE SEVERAL NARCOTIC DRUGS AND SUBSTANCES IN CIGARETTE SMOKE ARE ABLE TO REDUCE PLACENTAL 09 TRANSFER ACUTELY. WHEN THE! AVAILABILITY OF 02 TO THE FETUS IS LIMITED BY PHYSICAL b FACTORS, COMPENSATION BY THE FETUS WILL TAKE THE FORM OF A REDUCED GROWTH RATE IN THE LAST TRIMESTER." IN THE CRITICAL DISCUSSION WHICH FOLLOWED PRESENTATION OF THE PAPER, MANNERING OF THE UNIVERSITY OF MINNESOTA COMMENTED: "QNE COULD JUST AS WELL PREDICT THAT SMOKING MOTHERS MIGHT TRANSFER OXYGEN ACROSS THE PLACENTA MORE READILY THAN NONSMOKING MOTHERS BECAUSE THEIR PLACENTAS CONTAIN A GREAT DEAL MORE BENZPYRENE HYDROXYLASE ACTIVITY, AND THUS PRESUMABLY, MORE CYTOCHRO~E P-qS0, OR MORE LIKELY, CYTOCHROME P~-~S0.# THE RESULTS "INDICATE THAT TIlE TRANSPORT MECHANISMS FOR 02 AND CO IN THE PLACENTA AND LUNG ARE SIMILAR AND MAY INVOLVE THE SAME CARRIER MOLECULE IN EACH INSTANCE.... #ALTHOUGH ONLY A SINGLE COMPONENT OF THE TAR FRACTION FROM CIGARETTE SMOKE HAS BEEN TESTED, AND THE AMOUNTS OF ~,~-BENZO- PYRENE (500 MG) ADMINISTERED WERE GREATER THAN WOULD BE OBTAINED O,.~y CIR 98 CDHE 01

HKO270084 35625 FROM SMOKING 20 CIGARETTE~, THE REMAINING TARS (10-20 MG/CIGARETTE) MAY ALSO BIND THE PLACENTAL OXYGEN CARRIER AND INTERFERE HITH OXYGEN TRANSPORT, THE SUM TOTAL OF THE TARS IN 20 CIGARETTES APPROACHES THE AMOUNTS OF ~,4-BENZOPYRENE GIVEN IN OUR EXPERIMENTS," /BW/ JOHNS HOPK U SCH HYG PUBL HEALTH., BALTIMnR£, MD/ JOHNS HOPK U SCH HYG PUBL HEALTH, BALTIMORE, MD PHYSIOLOGICAL STUDY A, PHARMACOLOGICAL STUDY A, DOGS, SHEEP, OXYGEN TRANSPORT A, LUNG DIFFUSING CAPACITY A, CARBON MONOXIDE DIFFUSING CAPACITY A, PLACENTAL TRANSFER A, ~ICOTINE PHYSIOLOGICAL EFFECTS A, BENZO A PYRENE A, DRUG ACTION MECHANISMS A, BIOCHEMICAL MECHANISMS A, PLACENTA PERMEABILITY A/ mONGREL DOGS, CHLORPROMAZINE A, AHPHETAMINE A, IMIPRAHINE A, SKF 525A A, CYTOCHROME P 450, ANIMAL MODEL EXTRAPOLATION, NICOTINE PHYSIOLOGICAL EFFECTS A HI, SMOKING PHYSIOLOGICAL EFFECTS HI, HEALTH HAZARDS MATERNAL SMOKING CAUSATION 2 HI, PLACENTA BENZO A PYRENE HYDROXYLASE His HICOTINE DOSE A HI, PLACENTAL TRANSFER ~ l!I, CIGARETTE SMOKING, CIGARETTE BENZO A PYRENE CONTENT HI, INTERPRETATION VALIDITY CONCESSION, INTERPRETATION. VALIDITY HI, DRUG ADDICTION, BIRTH WEIGHT DECREASE, FETAL HYPOXIA[. INTRAVENOUS INJECTION A, CARBON MONOXIDE REBREATHING METHOD, PERFUSION A, LUNG EMPHYSEMA, ARGON A, ~ASS SPECTROMETRY, CAPILLARY BLOOD FLOW A, CARBON MONOXIDE TOXICITY A/ ENGLISH LANGUAGE, BALTIMORE MD RESIDENCE, USA RESIDENCE CTR 98 COl'J6 0'1038