Mel& PhlP in touds &d b&lUds v&deve&d ulihsing gas chromat~raphvlmass wectromelv with stable ~e.otope labelled an.+ logues as intemll s!anda,ds. In these studies it is demonstraled Ihat both MelDx and PhlP are well absorb& and eaensivetv metabolized following ingestkx of amme-containing bee1 by humans Expenments with furafylline. a potent and selective inhlmo, of human CYPlA2. re vsalthat more than 90% ofMel&.xand 7O%of PhIPawN-hvdroxvlated NI Myo. probably p,e.¶ytem,caiiy I” the live,

Nephroroxicb is often obsewod as an endpomt m ammal toxr,n, stud- ies.ln,ecentyea,s.lhe mechanisms of biitransfwmation. whlchoften provide the basis for ,e~l loxlc~ty. have hn elucidated for a “view of compounds. These stud1.x. showed lhar nephrotorrcity 01 ehemi- E~IS is eirhe, due to accumulation of certain met&&es in the kii- ney and torthe, bioactivation o, due to intrarana, bioactnre.tii of tha oerent xambiobc. Both woes of mechamsms till be discussed us- ing two ,ele.vant samplea:~he pdychlorimted olefin hexwhlorobut~ diene and other haloolefins cause nacrasis Of the 5.3 lepment 01 Ihe

proximal tub&s: their wphromxicity is dependent on bwclwation reactions. In the live,, hexachkwcbutadiene is lra~40rmed by coniw

gatbn wlh glutathicns to (Spentachlwobuwimyll gltdathlone. This Sconiugate 15 pmcasaed by the ontymep of merupturic acid lormb lian to give ~--ace~S.pen~achlo,bolad~~~L~~~ine. which is a~ cumulated in the p,orimsl tubule c&s and deacetWed Ihere to gwe ,$-pn,=chlorobutad,s~~L~~,~~*. FurUurbiMtival~on mcaWyted bY renal oysteine conjugate p-tvase. Both the renal accumuktion W the wganic anio.t,a,wo,te,andlhe topog,aphicaWslnbutlonof cyr- teine conlugate j.lYase along I!!8 nephron are mafir determinants of organ and ceU selectivirv. tinylidene chladde O/W io whrotoxic in mice alter inhalation. but not after oral or intrapmitonerl wlmuuslrb lion. The nephrotoxiclty of VOC IS due to the s~leetwe exp,mton 01 an and,opcr&dependant cytochrome P450 in the proximal tub&s oi male mice. Thi enzyme orklims VDC to an a!sct,ophiB and i> not p,esam in female mice. but can ba induced ba androww treat- ment. The obae?&im of nephmloxici(y of WC aiter inhalanan onhl is dvtr to ths hiih Mood flow lo the kiiney and tlws hiih concenlra- ,io,~s o, VM: delivered to the kidney afta ,nhllatiin AHe, oral OT IIC t,apatitcmeat appliiation. hepadc liwpsss metaww afficlenttv re dUceS the amount of VDC deliwed to the kidney The resuhs demon- strated here demonetrare that pno, to in “~“0 .eph,otowW saeen- inp. toxicokkketicr and bioiransfomntion pathway3 for a Chemical hwa

to be &cidated and metaboliiea have to be included into the tasting regiman.